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Practical Surgical Neuropathy—a volume in the new Pattern Recognition series— offers you a practical guide to solving the problems you encounter in the surgical reporting room. Drs. Arie Perry and Daniel J. Brat present diagnoses according to a pattern-based organization that guides you from a histological pattern, through the appropriate work-up, around the pitfalls, and to the best diagnosis. Lavish illustrations capture key neuropathological patterns for a full range of common and rare conditions, and a "visual index" at the beginning of the book directs you to the exact location of in-depth diagnostic guidance. No other single source delivers the practical, hands-on information you need to solve even the toughest diagnostic challenges in neuropathology.

  • Provides all the information essential for completing a sign-out report: clinical findings, pathologic findings, diagnosis, treatment, and prognosis.
  • Illustrates key pathologic and clinical aspects of disease entities through over 1430 superb, high-quality full-color images that help you evaluate and interpret biopsy samples.
  • Presents a team of internationally recognized experts for authoritative and up-to-date information from leading diagnosticians in neuropathology.
  • Features a user-friendly design with patterns color-coded to specific entities in the table of context and text and key points summarized in tables, charts, and graphs so you can quickly and easily find what you are looking for.
  • Directs you to the chapter and specific page number of the in-depth diagnostic guidance you need through a unique, pattern-based visual index at the beginning of the book.
  • Details key diagnostic features associated with rare and esoteric conditions in a visual encyclopedia with distinctive findings and artifacts for unusual patterns at the end of the book.


Neurofibromatosis type II
In Debt
Malignant peripheral nerve sheath tumor
Krabbe disease
Progressive supranuclear palsy
Chapter (books)
Traumatic brain injury
Glioblastoma multiforme
Vestibular schwannoma
Pituitary adenoma
Differential diagnosis
Acute lymphoblastic leukemia
Demyelinating disease
Subarachnoid hemorrhage
Tuberous sclerosis
Renal cell carcinoma
Medical imaging
Atkins diet
Non-Hodgkin lymphoma
Pituitary gland
Hodgkin's lymphoma
Parkinson's disease
Alzheimer's disease
Pulmonary pathology
Optic nerve glioma
Primary central nervous system lymphoma
Temporal lobe epilepsy
Embryonal carcinoma
Cerebral hemorrhage
X-ray computed tomography
Multiple sclerosis
Brain tumor
World Health Organization
White matter
Transient ischemic attack
Data storage device
Epileptic seizure
Radiation therapy
Peripheral nervous system
Optic neuritis
Magnetic resonance imaging
General surgery
Chemical element
Brain abscess


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Date de parution 16 avril 2010
Nombre de visites sur la page 0
EAN13 9781455706006
Langue English

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Practical Surgical
A Diagnostic Approach
Arie Perry, MD
Professor of Pathology and Neurological Surgery, Vice Chair, Department of Pathology,
Director of Neuropathology Division and the Neuropathology, Fellowship Program,
University of California at San Francisco (UCSF), San Francisco, California
Daniel J. Brat, MD, PhD
Professor and Vice Chair, Translational Programs, Director, Division of Neuropathology,
Department of Pathology and Laboratory Medicine, Emory University School of Medicine,
Atlanta, GeorgiaTable of Contents
Cover image
Title page
Series Preface
Practical Surgical Neuropathology Major Patterns
Chapter 1: Neuropathology Patterns and Introduction
Central Nervous System Tumor Classification Schemes and Additional
“Neuropathology Patterns”
Electron Microscopy
Molecular Diagnostics
Chapter 2: Normal Brain Histopathology
Cell Types
Tissue Organization
Features of Infancy and Childhood
Features of the Aging Nervous System
Chapter 3: Intraoperative Consultation and Optimal ProcessingTypes of Neurosurgical Specimens
Intraoperative Cytologic Preparations as a Complement to Frozen Tissue Sections
Fixation and Staining Options for Intraoperative Cytologic Preparations
Frozen Sectioning of Central Nervous System Tissue
Iatrogenically Introduced Hemostatic and Embolic Agents
The Bottom Line: What Does the Surgeon Need to Know?
Chapter 4: Neuroradiology: The Surrogate of Gross Neuropathology
Basic Noninvasive Diagnostic Imaging Techniques
Advanced Noninvasive Diagnostic Imaging Techniques
Basic Invasive Diagnostic Imaging Techniques
Advanced Invasive Therapeutic Techniques
Imaging Patterns in Neuroradiology
Advanced Strategies of Lesion Analysis
Chapter 5: Astrocytic and Oligodendroglial Tumors
Introduction and Brief Historical Overview
Diffuse Astrocytomas
Pilocytic Astrocytoma
Subependymal Giant-Cell Astrocytoma
Pleomorphic Xanthoastrocytoma
Chapter 6: Ependymomas and Choroid Plexus Tumors
Definitions and Synonyms
Brief Historical Overview
Ependymal Tumors
Choroid Plexus TumorsChapter 7: Neuronal and Glioneuronal Neoplasms
Gangliogliomas and Gangliocytomas (“Ganglion Cell Tumors”)
Desmoplastic Infantile Astrocytoma and Ganglioglioma
Dysplastic Gangliocytoma of the Cerebellum (Lhermitte-Duclos Disease)
Central Neurocytoma and Other Neurocytic Neoplasms
Cerebellar Liponeurocytoma
Dysembryoplastic Neuroepithelial Tumor
Papillary Glioneuronal Tumor
Rosette-Forming Glioneuronal Tumor of the Fourth Ventricle
Hypothalamic Hamartoma
Chapter 8: Pineal Parenchymal Tumors
Introduction, Definitions, and Synonyms
Brief Historical Overview
Incidence and Demographics
Localization and Clinical Manifestations
Radiologic Features and Gross Pathology
Histologic Variants and Grading
Principles of Diagnosis and Grading on Small or Artifact-Ridden Samples
Differential Diagnosis
Ancillary Diagnostic Studies
Treatment and Prognosis
Chapter 9: Embryonal (Primitive) Neoplasms of the Central Nervous System
Definition and Synonyms
Brief Historical Overview
Medulloblastoma (Cerebellar Primitive Neuroectodermal Tumor)
Central Nervous System Supratentorial Primitive Neuroectodermal Tumors and
Related Embryonal Neoplasms
Atypical Teratoid Rhabdoid TumorChapter 10: Meningiomas
Benign Meningioma (WHO Grade I)
Atypical Meningioma (WHO Grade II) (either of two major criteria)
Brain-Invasive Meningioma (WHO Grade II)
Anaplastic (Malignant) Meningioma (WHO Grade III) (either of two criteria)
Introduction and Proposed Etiologies
Definition and Analogies with Meningothelial Cells
Brief Historical Overview of Nomenclature and Histogenetic Notions
Meningiomas That Are Mostly Benign (WHO Grade I)
WHO Grade II Meningiomas
WHO Grade III (Malignant) Meningiomas
Chapter 11: Mesenchymal Tumors of the Central Nervous System
Brief Historical Overview
Incidence and Demographics
Lipoma and Liposarcoma
Fibroblastic–Myofibroblastic Tumors
Smooth Muscle Tumors
Skeletal Muscle Tumors
Vascular Tumors
Bone Tumors
Chondromatous Tumors
Undifferentiated Sarcoma
Miscellaneous Tumors and Tumor-like Lesions
Chapter 12: Peripheral Nerve Sheath Tumors
Traumatic Neuroma
Granular Cell Tumor
Miscellaneous Benign Neurogenic Tumors
Primary Malignant Tumors of Nerve
Malignant Granular Cell Tumor
Primitive Neuroectodermal Tumor of the Nerve
Chapter 13: Epithelial, Neuroendocrine, and Metastatic Lesions
Metastatic Epithelial and Epithelioid Neoplasms
Papillary Tumor of the Pineal Region
Cysts of the Central Nervous System
Chapter 14: Lymphomas and Histiocytic Tumors
Definition and Synonyms
Histiocytic Disorders
Chapter 15: Germ Cell Tumors
Definition and Synonyms
Brief Historical Overview
Incidence and Demographics
Clinical Manifestations and Localization
Radiologic Features and Gross Pathology
Histologic Variants
Ancillary Diagnostic Studies
Differential Diagnosis
Treatment and Prognosis
Germ Cell Tumors Metastatic to the Central Nervous SystemChapter 16: Melanocytic Neoplasms of the Central Nervous System
Definitions and Synonyms
Brief Historical Overview
Melanocytoma and Melanoma
Neurocutaneous Melanosis/Melanomatosis
Chapter 17: Other Glial Neoplasms
Angiocentric Glioma
Chordoid Glioma
Chapter 18: Pathology of the Pituitary and Sellar Region
The Sellar Region and Normal Pituitary
Anterior Pituitary Tumors
Invasion and Malignancy in Anterior Pituitary Tumors
Pituitary Hyperplasia
Other Primary Pituitary Tumors
Miscellaneous Sellar Region Tumors
Sellar Region Cysts
Inflammatory Lesions
Infectious Lesions
Chapter 19: Therapy-Associated Neuropathology
Radiation Necrosis and Other Forms of Radiation Injury
Therapy-Induced Leukoencephalopathies and Vasculopathies
Therapy-Induced Secondary Neoplasms
Chapter 20: Familial Tumor Syndromes
Neurofibromatosis Type 1
Neurofibromatosis Type 2
SchwannomatosisTuberous Sclerosis Complex
Von Hippel-Lindau Disease
Turcot Syndrome
Nevoid Basal Cell Carcinoma Syndrome (Gorlin Syndrome)
Cowden Disease
Li-Fraumeni Syndrome
Carney Complex
Rhabdoid Predisposition Syndrome
Other Syndromes
Chapter 21: Infections and Inflammatory Disorders
Focal Discrete Central Nervous System Infection
Inflammatory Conditions of the Nervous System Mimicking Infections
Central Nervous System Manifestations of Rheumatoid Arthritis
Central Nervous System Manifestations of Wegener Granulomatosis
Chapter 22: White Matter and Myelin Disorders
Multiple Sclerosis
Neuromyelitis Optica
Acute Disseminated Encephalomyelitis
Acute Hemorrhagic Leukoencephalitis
Progressive Multifocal Leukoencephalopathy
Subacute Sclerosing Panencephalitis
HIV Leukoencepahlopathy and Vacuolar Myelopathy
Binswanger Encephalopathy
Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and
Fat EmbolismLeukodystrophies
Osmotic Demyelination Syndrome (Central Pontine and Extrapontine Myelinolysis)
Chapter 23: Pathology of Epilepsy
Malformations of Cortical Development (Cortical Dysplasia)
Hippocampal Sclerosis
Infarct Including Porencephalic Cyst
Rasmussen Encephalitis
Chapter 24: Vascular and Ischemic Disorders
Ischemic Cerebral Infarct
Hypertensive Cerebrovascular Disease
Cerebral Amyloid Angiopathy
Vasculitis Involving the Nervous System
Giant-Cell Arteritis
Primary Angiitis of the Central Nervous System
Polyarteritis Nodosa
Cerebral Aneurysms
Fusiform and Infective (“Mycotic”) Aneurysms
Vascular Malformations
Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and
Moyamoya Syndrome
Chapter 25: Biopsy Pathology of Neurodegenerative Disorders in Adults
Alzheimer Disease
Dementia with Lewy Bodies and Idiopathic Parkinson Disease
Frontotemporal Lobar Degeneration and Pick Disease
Human Prion Diseases (Transmissible Spongiform Encephalopathies) Including
Creutzfeldt-Jakob Disease
C o p y r i g h t
ISBN: 978-0-443-06982-6
© 2010 by Churchill Livingstone an affiliate of Elsevier Inc. All rights reserved.
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Library of Congress Cataloging-in-Publication Data
Practical surgical neuropathology : a diagnostic approach / [edited by] Arie Perry, Daniel J. Brat.
p. ; cm.
Includes index.
ISBN 978-0-443-06982-6
1. Brain–Tumors–Diagnosis. 2. Nervous system–Diseases–Diagnosis. 3. Pathology, Surgical. I. Perry, Arie.
II. Brat, Daniel J. III. Title.
[DNLM: 1. Nervous System Diseases–surgery. 2. Nervous System Diseases–pathology. 3. Pathology,
Surgical–methods. WL 368 P8947 2010]
RC280.B7P723 2010616.99′481–dc22
Acquisitions Editor: William Schmitt
Publishing Services Manager: Joan Sinclair
Printed in China
Last digit is the print number: 9 8 7 6 5 4 3 2 1Contributors
Daniel J. Brat, MD, PhD, Professor and Vice Chair, Translational Programs,
Director, Division of Neuropathology, Department of Pathology and Laboratory
Medicine, Emory University School of Medicine, Atlanta, Georgia
David A. Decker, MD, Department of Neurology, University of Florida College of
Medicine, McKnight Brain Institute, Gainesville, Florida
Michelle Fèvre-Montange, PhD, Université de Lyon, Lyon, France
Christine E. Fuller, MD, Professor of Pathology, Director of Neuropathology and
Autopsy Pathology, Medical College of Virginia/Virginia Commonwealth University,
Richmond, Virginia
Gregory N. Fuller, MD, PhD, Professor of Pathology (Neuropathology), The
University of Texas Graduate School of Biomedical Sciences, Professor and Chief
Section of Neuropathology, The University of Texas M.D. Anderson Cancer Center,
Houston, Texas
Eyas M. Hattab, MD, Associate Professor, Department of Pathology and
Laboratory Medicine, Indiana University School of Medicine, Medical Director,
Immunohistochemistry Laboratory, Clarian Pathology Library, Indianapolis, Indiana
Eva Horvath, PhD, Pathology Consultant, Endocrine Pathology Research, St.
Michael’s Hospital, Toronto, Ontario, Canada
Anne Jouvet, MD, PhD, Associate Professor of Pathology, Centre de Pathologie et
Neuropathologie EST, Groupement Hospitalier EST, Hospices Civils de Lyon, Lyon,
Scott E. Kilpatrick, MD, Pathologists Diagnostic Services, Forsyth Medical Center,
Winston-Salem, North Carolina
B.K. Kleinschmidt-DeMasters, MD, Professor and Head, Division of
Neuropathology, Department of Pathology, University of Colorado Health Science
Center, Denver, Colorado
Kalman Kovacs, MD, PhD, Professor of Pathology, Department of Laboratory
Medicine, St. Michael’s Hospital, University of Toronto, Toronto, Ontario, Canada
M. Joe Ma, MD, PhD, Assistant Professor of Pathology, Department of Medical
Education, University of Central Florida College of Medicine, Pathologist,Department of Pathology, Florida Hospital—Orlando, Orlando, Florida
Ricardo V. Lloyd, MD, Professor of Pathology, Department of Anatomic
Pathology, Mayo College of Medicine, Rochester, Minnesota
Sonia Narendra, MD, Pathology Resident, SUNY Upstate Medical University,
Syracuse, New York
Werner Paulus, MD, Professor of Neuropathology, University of Muenster,
Director Institute of Neuropathology, University Hospital Muenster, Muenster,
Arie Perry, MD, Professor of Pathology and Neurological Surgery, Vice Chair,
Department of Pathology, Director of Neuropathology Division and the
Neuropathology Fellowship Program, University of California at San Francisco
(UCSF), San Francisco, California
Richard A. Prayson, MD, Head, Section of Neuropathology, Department of
Anatomic Pathology, Cleveland Clinic Foundation, Cleveland, Ohio
Bernd W. Scheithauer, MD, Professor of Pathology, Department of Anatomic
Pathology, Mayo College of Medicine, Consultant, Mayo Clinic, Rochester,
Robert E. Schmidt, MD, PhD, Professor and Chief, Division of Neuropathology,
Washington University School of Medicine, St. Louis, Missouri
Ana I. Silva, MD, Hospital Assistant, Department of Anatomic Pathology, Hospital
São Marcos, Graga, Protugal
Robert J. Spinner, MD, Professor, Neurologic Surgery, Orthopedics and Anatomy,
Mayo Clinic, Rochester, Minnesota
Tarik Tihan, MD, PhD, Professor, Department of Pathology, University of
California San Francisco, San Francisco, California
Kenneth L. Tyler, MD, Reuler-Lewin Family Professor of Neurology and Professor
of Medicine and Microbiology, Departments of Neurology, Medicine, Microbiology,
University of Colorado Denver Health Sciences Center, Neurology Service, Denver VA
Medical Center, Denver, Colorado
Alexandre Vasiljevic, MD, Centre de Pathologie et Neuropathologie EST,
Groupement Hospitalier EST, Hospices Civils de Lyon, Lyon, France
Franz J. Wippold, II, MD
Professor and Chief, Neuroradiology Section, Mallinckrodt Institute of Radiology,
Washington University School of Medicine, Attending Neuroradiologist,
BarnesJewish Hospital, Attending Neuroradiologist, St. Louis Children’s Hospital, St. Louis,
Adjunct Professor of Radiology/Radiological Sciences, F. Edward Hérbert School ofMedicine, Uniformed Services University of the Health Sciences, Bethesda, Maryland
James M. Woodruff, MD, Emeritus Attending Physician, Department of
Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York
Anthony T. Yachnis, MD, Professor and Director of Anatomic Pathology,
Department of Pathology, Immunology, and Laboratory Medicine, University of
Florida College of Medicine, Gainesville, Florida'
Series Preface
Kevin O. Leslie, MD and Mark R. Wick, MD
It is often stated that anatomic pathologists come in two forms: “Gestalt”-based
individuals, who recognize visual scenes as a whole, matching them unconsciously
with memorialized archives; and criterion-oriented people, who work through images
systematically in segments, tabulating the results—internally, mentally, and quickly
—as they go along in examining a visual target. These approaches can be equally
e ective, and they are probably not as dissimilar as their descriptions would suggest.
In reality, even “Gestaltists” subliminally examine details of an image, and, if asked
speci cally about particular features of it, they are able to say whether one
characteristic or another is important diagnostically.
In accordance with these concepts, in 2004 we published a textbook entitled
Practical Pulmonary Pathology: A Diagnostic Approach (PPPDA). That monograph was
designed around a pattern-based method, wherein diseases of the lung were divided
into six categories on the basis of their general image pro les. Using that technique,
one can successfully segregate pathologic conditions into diagnostically and
clinically useful groupings.
The merits of such a procedure have been validated empirically by the enthusiastic
feedback we have received from users of our book. In addition, following the old
adage that “imitation is the sincerest form of attery,” since our book came out other
publications and presentations have appeared in our specialty with the same
After publication of the PPPDA text, representatives at Elsevier, most notably'
William Schmitt, were enthusiastic about building a series of texts around
patternbased diagnosis in pathology. To this end we have recruited a distinguished group of
authors and editors to accomplish that task. Because a panoply of patterns is di cult
to approach mentally from a practical perspective, we have asked our contributors
to be complete and yet to discuss only principal interpretative images. Our goal is
eventually to provide a series of monographs which, in combination with one
another, will allow trainees and practitioners in pathology to use salient
morphological patterns to reach with con dence nal diagnoses in all organ
As stated in the introduction to the PPPDA text, the evaluation of dominant
patterns is aided secondarily by the analysis of cellular composition and other
distinctive ndings. Therefore, within the context of each pattern, editors have been
asked to use such data to refer the reader to appropriate speci c chapters in their
respective texts.
We have also stated previously that some overlap is expected between pathologic
patterns in any given anatomic site; in addition, speci c disease states may
potentially manifest themselves with more than one pattern. At rst, those facts may
seem to militate against the value of pattern-based interpretation. However,
pragmatically, they do not. One often can narrow diagnostic possibilities to a very
few entities using the pattern method, and sometimes a single interpretation will be
obvious. Both of those outcomes are useful to clinical physicians caring for a given
It is hoped that the expertise of our authors and editors, together with the high
quality of morphologic images they present in this Elsevier series, will be bene cial
to our reader-colleagues.%
P r e f a c e
Arie Perry, MD and Daniel J. Brat, MD, PhD
When Kevin Leslie and Mark Wick approached us a few years ago to write a new
neuropathology textbook for a patterns-oriented organ-based series, it was with
some trepidation that we ultimately accepted. After all, there are already some
excellent texts available on this topic, and we have both contributed chapters to
some of these in the past. However, the patterns approach used in the Leslie and Wick
Practical Pulmonary Pathology book is somewhat novel, and we were not aware of
others placing a major emphasis on this tactic toward neuropathology diagnosis. As
our work progressed, we found additional ways of enhancing the reader’s experience
and we are quite excited about the nal product! Our primary target audience is the
general surgical pathologist and pathology trainees. However, while we focused
most on common issues of surgical neuropathology, rarer entities and
clinicopathologic correlations are also well covered and illustrated. Therefore, we
believe that this book will also be useful to neuropathologists and clinical colleagues
from related medical specialties such as neurosurgery, neurology, neuroradiology,
neuro-oncology, and pediatrics. In order to readdress the important question of why
one should buy yet another neuropathology textbook, we provide the following list
of strengths.
• Patterns-based diagnostic approaches: In addition to offering the traditionaldisease-based approach to nervous system pathology (Chapters 5 through 25), this
book provides instructive algorithms based on 8 major (scanning magnification)
patterns (immediately following the introduction) and 20 minor (higher
magnification) patterns (Chapter 1). This material can be particularly helpful to
less experienced morphologists who may feel lost or overwhelmed by the myriad
diagnostic possibilities. After the reader obtains an appropriately focused
differential, he or she can quickly turn to more detailed discussions of specific
entities in later chapters of the book. Alternatively, one can start with basic
clinicoradiologic patterns combining patient age, location, and neuroimaging
features to create a differential diagnosis (Table 1-1). In fact, these two
approaches are easily combined to further narrow the differential. To further
enhance this strategy, the key clinicopathologic features for 21 common
differentials and the immunoprofiles for 26 common tumors are summarized in
Tables 1-3 and 1-4, respectively. Major neuroimaging patterns are listed in Box 4-1.
• Background data: The nervous system is particularly challenging because of its
remarkable anatomic and cellular complexity. For instance, the histology changes
completely from one area to another, engendering diverse diagnostic differentials
depending on the site of involvement. Therefore, a review of basic neuroanatomy
and histopathology may help (Chapter 2). In addition, the use of ancillary
techniques is rapidly evolving, and therefore an overview of
immunohistochemistry, electron microscopy, and molecular diagnostics is
provided in Chapter 1.
• Intraoperative consultation and optimal processing: Nothing seems to
provoke a panic attack more reliably than the “neuro frozen,” yet there is often
little practical guidance available for this common setting. Furthermore, artifacts
induced by frozen sections and many other procedures implemented by either the
neurosurgeon or the pathologist can present serious pitfalls and may preclude an
accurate diagnosis. These important topics are discussed in Chapter 3.
• Neuroradiology: As will be mentioned several times in this book, neuroradiology
increasingly provides the most relevant gross pathology for nervous system biopsy
interpretation, particularly when the tissue sample is small. In this context the
pathologist must become at least an amateur neuroradiologist so that important
radiologic-pathologic correlations are not missed. This critical topic is summarized
and illustrated in Chapter 4.
• The authors: In addition to being international authorities on their topics, the
authors were carefully selected for their clarity and enthusiasm for teaching. They
are highly sought conference speakers, writers, and recipients of teaching awards.
One is also known for a somewhat unconventional but highly popular teaching
method. Dr. Perry’s innovative use of “neuropathology songs” to help medical
students remember key features of neurological disorders has been the topic ofseveral newspaper and radio reports. By the time this book is published, a CD
recording should be complete and readers interested in a fun approach to
musically reinforcing their knowledge base should visit
• The images: One can scarcely find a more visually oriented medical specialty
than pathology. Therefore, if the average picture is worth 1000 words, then the
average pathology picture must be worth at least 10,000. With this in mind, we
took great care to find the best images possible, making sure that the text is amply
illustrated with generously sized high-quality figures. Given the focus of this book on
surgical neuropathology, most of the “gross photos” are naturally magnetic
resonance images. Nonetheless, we did not hesitate to utilize some postmortem
photos and discussions when these clearly enhanced the reader’s understanding.
This was particularly true for the infectious/inflammatory, vascular, and
neurodegenerative disorders covered in Chapters 21 24, and 25, respectively.
• The text: In order to highlight the most salient features of each disorder, italics are
used throughout the text for quick reference, as are helpful summary tables and
We have endeavored to create a practical guide for those who work with biopsies
of the nervous system and the patients from whom they were derived. We sincerely
hope that you find it useful and enjoyable.7

A c k n o w l e d g m e n t s
Arie Perry, MD and Daniel J. Brat, MD, PhD
As with any project of this magnitude, it simply can’t be done alone. I am
extremely grateful to my talented coeditor, Dan Brat, and to all my wonderful
coauthors for injecting countless hours of additional time and e ort into their
already busy schedules in order to create an exceptional product. For any diagnostic
prowess I may possess, I owe an incredible debt to my surgical neuropathology
mentor, Bernd Scheithauer of the Mayo Clinic, as most of my “pearls of wisdom” are
easily traced back to him. I was particularly thrilled that he agreed to contribute two
chapters on topics for which he is clearly one of the world’s authorities: pituitary
pathology and peripheral nerve sheath tumors. For autopsy neuropathology, Joe
Parisi was an equally outstanding mentor. In addition, I would especially like to
thank Robert Schmidt for being such a remarkably supportive “boss” and close friend
over my 12 years at Washington University in St. Louis. I particularly enjoyed our
cordial competitions over who could shoot (and improve with Adobe Photoshop) the
best photomicrographs (Bob: I think I won!). Particularly useful for this book was our
practice of sharing with one another images from interesting cases as they came
through our clinical service. A number of Bob’s masterpieces are sprinkled
throughout several chapters and perhaps a few of mine have snuck into his chapter.
Special thanks also go to Franz (“Jay”) Wippold of the Mallinckrodt Institute for
Radiology with whom I’ve coauthored several review articles for a series entitled
“Neuropathology for the Neuroradiologist.” It seems only tting that he now o ers
his remarkable expertise to teach us some basic “neuroradiology for the
neuropathologist.” In broader terms, I’d like to thank my parents, Gabriel and
Bathsheba, for their incredible support and for giving me an innate desire to excel.
My brother Ron similarly supported me through some challenging times. Lastly, I’m
eternally grateful to my wife, Andrea, and my kids, Ryan and Jaclyn, for putting up
with me and my long hours at work over the last few years.
The writing and editing of a comprehensive and authoritative textbook should not
be entertained by the impatient or the faint of heart. Because of his wealth of
knowledge, high standards, persistence, and overall good nature, I can think of no
better collaborator on such an e ort than Arie Perry. I look forward to updated
editions as well as new neuropathology songs in the years to come. The collection of
authors that we were able to gently persuade to contribute to this text is truly7


impressive. They deserve our deepest appreciation for allowing us to tap into their
hard-earned expertise for this project. For their e orts, I hope this text will be widely
acknowledged for the excellence it brings to the eld of neuropathology. My own
abilities to assist in this e ort are directly attributed to those who drew me into
neuropathology and to those who trained me both in person and at a distance. Joe
Parisi and Bernd Scheithauer were larger than life gures that attracted a young
medical student at the Mayo Clinic into the eld of neuropathology and have
continued to be role models. Peter Burger provided mentorship and enormous
opportunity during residency and fellowship at Johns Hopkins Hospital and is most
responsible for any academic successes I have had or will have. Finally, the family of
Brats has always been a source of stability, inspiration, and thorough entertainment.
Thanks to Paul, Dave, Jim, and Nancy Elaine.Practical Surgical Neuropathology Major Patterns
Pattern Diseases to Be Considered
Parenchymal infiltrate with Diffuse glioma
hypercellularity CNS lymphoma
Active demyelinating disease
Cerebral infarct
Reactive gliosis
Solid mass (pure) Metastasis
Subependymal giant-cell astrocytoma (SEGA)
Central or extraventricular neurocytoma
Embryonal tumor (e.g., AT/RT)
Choroid plexus papilloma
Pituitary adenoma
Solid and infiltrative process Pilocytic astrocytoma
Pleomorphic xanthoastrocytoma
Glioblastoma/gliosarcoma (and other high grade gliomas)
Dysembryoplastic neuroepithelial tumor (DNT)
Embryonal tumor (e.g., medulloblastoma/CNS PNET)
Choroid plexus carcinoma
Germ cell tumors
CNS lymphoma
Histiocytic disorders
Abscess and other forms of infection
Vasculocentric process CNS lymphoma
Intravascular lymphoma
Angiocentric glioma
Active demyelinating disease
Amyloid angiopathy
Cerebral autosomal dominant arteriopathy with subcortical infarcts and
leukoencephalopathy (CADASIL)
Vascular malformations
Infections (e.g., aspergillosis)
Thromboembolic disease
Extra-axial mass Meningioma
Solitary fibrous tumor
Schwannoma and other nerve sheath tumors
Melanoma or melanocytoma
Secondary lymphoma or leukemiaParaganglioma
Pattern Diseases to Be Considered
Pituitary adenoma
Granulomatous infections
Inflammatory pseudotumors
Calcifying pseudotumor of the neuraxis
Primary bone tumors (e.g., chordoma)
Histiocytic disorders (e.g., Rosai-Dorfman disease)
Meningeal infiltrate Meningeal carcinomatosis, gliomatosis, melanosis, melanomatosis, sarcomatosis, or
Metastatic medulloblastoma/CNS PNET
Secondary lymphoma or leukemia
Histiocytic disorders
Infectious granulomatous diseases
Collagen vascular disorders
Sturge-Weber syndrome
Destructive/necrotic process Cerebral infarct
Radiation necrosis or treatment effects
CNS lymphoma in an immunosuppressed patient
Intravascular lymphoma
Severe demyelinating disease
Metabolic/toxic disease
Subtle pathology or near-normal Nonrepresentative biopsy specimen
biopsy Subtle diffuse glioma (WHO grade II)
Hypothalamic hamartoma
Cortical dysplasia or tuber
Mesial temporal sclerosis
Intravascular lymphoma
Mild encephalitis
Cerebral malaria
Ischemic disease
Neurodegenerative diseases
Benign cysts
Metabolic or toxic disorder
Reactive gliosis or “glial scar”
Pattern 1 Parenchymal infiltrate with hypercellularityElements of the pattern: The brain biopsy specimen shows intact cortical architecture, but a hypercellular infiltrate is
evident at scanning magnification. In this particular example, an additional finding is secondary structure formation, with
subpial condensation, perivascular aggregates, and perineuronal satellitosis. This growth pattern is most common in
diffuse gliomas.Additional Findings Diagnostic Considerations Chapter:page
Secondary structures of Scherer Diffuse gliomas Ch. 5:63
Extensive bilateral cerebral involvement Gliomatosis cerebri Ch. 5:71, 80
Lymphomatosis cerebri Ch. 14:316
Angiocentric pattern CNS lymphoma Ch. 14:315
Angiocentric glioma Ch. 17:361
Meningoencephalitis/Infections Ch. 21:468
Active demyelinating disease Ch. 22:485
Microcystic pattern Diffuse gliomas Ch. 5:63
Pleomorphism Astrocytoma/glioblastoma Ch. 5:63
Infections, especially PML Ch. 21:470
Monomorphism Oligodendroglioma Ch. 5:93
Some lymphomas Ch. 14:315
Lymphocytic infiltrate Gemistocytic astrocytoma Ch. 5:70
CNS lymphoma Ch. 14:315
Meningoencephalitis/Infections Ch. 21:468
Active demyelinating disease Ch. 22:485
Foamy histiocytes CNS lymphoma Ch. 14:315
Active demyelinating disease Ch. 22:485
Cerebral infarct Ch. 24:528
Cytologic atypia or anaplasia Diffuse gliomas Ch. 5:63
CNS lymphoma Ch. 14:315
Viral inclusions or organisms Meningoencephalitis/Infections Ch. 21:468
None Reactive gliosis Ch. 1:8 Ch. 5:74
Pattern 2 Solid mass (pure)Elements of the pattern: The biopsy specimen shows a very sharply demarcated intracerebral mass. The increased
cellularity imparts a blue color to the tumor, whereas foci of central necrosis appear pink. An additional finding was gland
formation, consistent with metastatic adenocarcinoma.Additional Findings Diagnostic Considerations Chapter:page
Mucin-filled glands Metastatic adenocarcinoma Ch. 13:287
Perivascular pseudorosettes Subependymal giant-cell astrocytoma Ch. 5:88
Ependymoma Ch. 6:103
Central or extraventricular neurocytoma Ch. 7:135
Pineocytoma Ch. 8:152
Metastasis (neuroendocrine) Ch. 13:287
Paraganglioma Ch. 13:296
Pituitary adenoma Ch. 18:372
Nodularity Subependymoma Ch. 6:104
Metastasis (neuroendocrine) Ch. 13:287
Paraganglioma Ch. 13:296
Pituitary adenoma Ch. 18:372
Gliofibrillary processes Subependymal giant-cell astrocytoma Ch. 5:88
Ependymoma Ch. 6:103
Subependymoma Ch. 6:104
Papillary pattern Choroid plexus papilloma Ch. 6:113
Papillary ependymoma Ch. 6:106, 109
Metastatic carcinoma Ch. 13:287
Pituitary adenoma Ch. 18:372
Hypervascularity Choroid plexus papilloma Ch. 6:113
Hemangioblastoma Ch. 20:440
Neuropil/neuronal rosettes Central or extraventricular neurocytoma Ch. 7:135
Pineocytoma Ch. 8:152
Adjacent piloid gliosis Craniopharyngioma Ch. 18:402
Hemangioblastoma Ch. 20:440
Epithelioid cytology Choroid plexus papilloma Ch. 6:113
Metastatic carcinoma Ch. 13:287
Small primitive cells Embryonal tumor (AT/RT) Ch. 9:165, 179
Metastatic carcinoma (small cell) Ch. 13:287
Melanin pigment Melanoma (usually metastatic) Ch. 13:291 Ch. 6:353
Clear cells Clear cell ependymoma Ch. 6:107
Central or extraventricular neurocytoma Ch. 7:135
Pineocytoma Ch. 8:152
Hemangioblastoma Ch. 20:440
Metastatic carcinoma Ch. 13:287
Cytologic anaplasia Embryonal tumor (AT/RT) Ch. 9:165, 179
Metastatic carcinoma Ch. 13:287
Pattern 3 Solid and infiltrative processElements of the pattern: The biopsy specimen shows a mostly solid-appearing neoplasm (left half), but has fuzzy or
illdefined margins with the adjacent brain parenchyma, consistent with at least a partially infiltrative component as well (right
half, especially in white matter). Additional findings in this case were reticulin-rich spindled elements, GFAP-positive glial
elements, and pseudopalisading necrosis, consistent with gliosarcoma.Additional Findings Diagnostic Considerations Chapter:page
Biphasic growth (compact and microcystic), EGBs, Rosenthal fibers Pilocytic astrocytoma Ch. 5:82
Pleomorphic xanthoastrocytoma Ch. 5:91
Ganglioglioma Ch. 7:125
Dysembryoplastic neuroepithelial tumor Ch. 7:140
Pseudopalisading necrosis Glioblastoma or gliosarcoma Ch. 5:63, 66
Nodularity Anaplastic oligodendroglioma Ch. 5
Dysembryoplastic neuroepithelial tumor Ch. 7:140
Ganglioglioma Ch. 7:125
Desmoplastic or nodular medulloblastoma Ch. 9:169
Germinoma or germ cell tumors Ch. 15:336
Angiocentric pattern CNS lymphoma Ch. 14:315
Infections Ch. 21:477
Fascicles of spindled cells Gliosarcoma Ch. 5:70
Pleomorphic xanthoastrocytoma Ch. 5:91
Primary CNS sarcoma (rare) Ch. 11:219
Inflammation-rich Pleomorphic xanthoastrocytoma Ch. 5:91
Ganglioglioma Ch. 7:125
CNS lymphoma Ch. 14:315
Germinoma or germ cell tumors Ch. 15:336
Abscess and other infections Ch. 21:477
Adjacent piloid gliosis Pleomorphic xanthoastrocytoma Ch. 5:91
Craniopharyngioma Ch. 18:402
Glial cytology Pilocytic astrocytoma Ch. 5:82
Pleomorphic xanthoastrocytoma Ch. 5:91
Glioblastoma or gliosarcoma Ch. 5:63, 66
Ganglioglioma Ch. 7:125
Dysembryoplastic neuroepithelial tumor Ch. 7:140
Large ganglioid cells with vesicular nuclei and large nucleoli Pleomorphic xanthoastrocytoma Ch. 5:91
Ganglioglioma Ch. 7:125
Dysembryoplastic neuroepithelial tumor Ch. 7:140
CNS lymphoma (anaplastic large cell) Ch. 14:330
Germinoma Ch. 15:336
Epithelioid cytology Choroid plexus carcinoma Ch. 6:113
Germ cell tumors Ch. 15:333
Craniopharyngioma Ch. 18:402
Small primitive cells Choroid plexus carcinoma Ch. 6:113
Medulloblastoma/CNS PNET Ch. 9:165, 175
CNS lymphoma Ch. 14:315
Foamy cells Pleomorphic xanthoastrocytoma Ch. 5:91
Glioblastoma (occasionally) Ch. 5:63, 66
Histiocytic disorders Ch. 14:326
Infections Ch. 21:455
Pattern 4 Vasculocentric processElements of the pattern: The biopsy specimen shows a disease process that is clearly centered on blood vessels.
Additional findings in this case were foci of angionecrosis and vascular or perivascular inflammation, consistent with
vasculitis.Additional Findings Diagnostic Considerations Chapter:page
Perivascular or intravascular infiltrate CNS lymphoma Ch. 14:315
Meningoencephalitis/infection Ch. 21:468
Neurosarcoidosis Ch. 21:481
Active demyelinating disease Ch. 22:485
Vasculitis Ch. 24:537
Amyloid angiopathy with vasculitis Ch. 24:535
Intraluminal atypical cells Intravascular lymphoma Ch. 14:319
Perivascular glial or spindled cells Ependymoma Ch. 6:103
Angiocentric glioma Ch. 17:361
Meningioangiomatosis Ch. 20:433
Angionecrosis Infections (aspergillosis) Ch. 21:464
Vasculitis Ch. 24:537
Thromboembolic disease Ch. 24:528
Vascular hyalinization Meningioangiomatosis Ch. 20:433
Amyloid angiopathy Ch. 24:535
CADASIL Ch. 24:546
Arteriolosclerosis Ch. 24:533
Vasculitis Ch. 24:537
Vascular malformations Ch. 24:542
Granular vascular deposits CADASIL Ch. 24:546
Granulomas or giant cells Infections Ch. 21:455
Neurosarcoidosis Ch. 21:481
Vasculitis Ch. 24:537
Amyloid angiopathy with vasculitis Ch. 24:535
Cerebral hemorrhage Infections (aspergillosis) Ch. 21:464
Amyloid angiopathy Ch. 24:535
Vascular malformations Ch. 24:542
Cerebral infarcts or microinfarcts Intravascular lymphoma Ch. 14:319
Infections Ch. 21:455
Neurosarcoidosis Ch. 21:481
Vasculitis Ch. 24:537
Amyloid angiopahty Ch. 24:535
CADASIL Ch. 24:546
Arteriolosclerosis Ch. 24:533
Thromboembolic disease Ch. 24:528
Disorganized, irregular blood vessels Meningioangiomatosis Ch. 20:433
Vascular malformations Ch. 24:542
Pattern 5 Extra-axial massElements of the pattern: The biopsy specimen shows a solid mass attached to a strip of dura in the upper portion of the
image. Additional findings in this case were whorls of epithelioid cells and scattered psammoma bodies, consistent with
Additional Findings Diagnostic Considerations Chapter:page
Whorls or nests Meningioma Ch. 10:185
Chordoma Ch. 11:231
Schwannoma (occasionally) Ch. 12:240
Metastatic carcinoma Ch. 13:287
Paraganglioma Ch. 13:296
Melanocytoma Ch. 16:353
Psammoma bodies Meningioma Ch. 10:185
Psammomatous melanotic schwannoma Ch. 12:251
Metastatic carcinoma (rare) Ch. 13:287
Peripheral or cranial nerve involvement Pilocytic astrocytoma (optic pathway) Ch. 5:82
Orbital meningioma Ch. 10:185
Orbital sarcoma (rhabdomyosarcoma) Ch. 11:226
Schwannoma Ch. 12:240
Neurofibroma Ch. 12:251
Perineurioma Ch. 12:260
MPNST Ch. 12:272
Neurolymphomatosis Ch. 14:315
Biphasic (compact and loose) pattern with Verocay bodies Meningioma (rare) Ch. 10:185
Schwannoma Ch. 12:240
Hypervascular Angiomatous meningioma Ch. 10:194
Hemangiopericytoma Ch. 11:220
Hemangioblastoma Ch. 20:440
Gaping “staghorn” blood vessels Meningioma (rare) Ch. 10:185
Hemangiopericytoma Ch. 11:220
Solitary fibrous tumor Ch. 11:220
Alternating “dark and light” regions Hemangiopericytoma Ch. 11:220
Solitary fibrous tumor Ch. 11:220Dense bundles of eosinophilic collagen Clear cell meningioma Ch. 10:200
Additional Findings Diagnostic Considerations Chapter:page
Solitary fibrous tumor Ch. 11:220
Inflammatory infiltrate Lymphoplasmacyte-rich meningioma Ch. 10:198
Inflammatory myofibroblastic tumor Ch. 11:221
Secondary lymphoma/leukemia Ch. 14:321
Infections Ch. 21:455
Neurosarcoidosis Ch. 21:481
Collagen vascular disorders Ch. 21:481
Fibrillar to amorphous basophilic material Calcifying pseudoneoplasm of the neuraxis Ch. 10:211
Small primitive cells Hemangiopericytoma Ch. 11:220
Other sarcomas (EWS/pPNET) Ch. 11:233
Metastatic carcinoma (small cell) Ch. 13:287
Secondary lymphomas/leukemias Ch. 14:321
Large anaplastic cells Anaplastic meningioma Ch. 10:192, 203
Metastatic carcinoma Ch. 13:287
Anaplastic large cell lymphoma Ch. 14:320
Myeloid sarcoma Ch. 14:322
Melanoma Ch. 16:353
Epithelioid cells Meningioma Ch. 10:185
Metastatic carcinoma Ch. 13:287
Paraganglioma Ch. 13:296
Melanoma Ch. 16:353
Pituitary adenoma Ch. 18:372
Clear cells Clear cell meningioma Ch. 10:200
Hemangiopericytoma Ch. 11:220
Other sarcomas (leiomyosarcoma) Ch. 11:225
Metastatic carcinoma Ch. 13:287
Paraganglioma Ch. 13:296
Histiocytic disorders Ch. 14:326
Hemangioblastoma Ch. 20:440
Foamy cells Angiomatous meningioma Ch. 10:194
Schwannoma (histiocytes) Ch. 12:240
Histiocytic disorders Ch. 14:326
Hemangioblastoma Ch. 20:440
Granulomas or giant cells Infections (TB, fungal meningitis) Ch. 21:455
Neurosarcoidosis Ch. 21:481
Collagen vascular disorders Ch. 21:481
Pattern 6 Meningeal infiltrateElements of the pattern: The whole-mount brain section shows a markedly expanded subarachnoid space filled with blue
cells. At higher magnification, the infiltrate consisted predominantly of neutrophils, consistent with acute meningitis.
Additional Findings Diagnostic Considerations Chapter:page
Neoplastic cells Metastatic medulloblastoma/CNS PNET Ch. 9:165, 175
Meningeal sarcomatosis Ch. 11:220
Meningeal carcinomatosis Ch. 13:287
Secondary lymphoma/leukemia Ch. 14:321
Meningeal melanosis/melanomatosis Ch. 16:353, 357
Meningeal gliomatosis Ch. 21: 465
Venous malformation Sturge-Weber syndrome Ch. 20:451
Neutrophil-rich infiltrate Acute bacterial meningitis Ch. 21:456
Lymphoplasmacytic infiltrate Infectious meningitis Ch. 21:456
Chemical meningitis Ch. 21:465
Neurosarcoidosis Ch. 21:481
Collagen vascular disorder Ch. 21:481
Granulomas/giant cells Infectious meningitis (TB, fungal) Ch. 21:456
Neurosarcoidosis Ch. 21:481
Collagen vascular disorder Ch. 21:481
Clear to foamy cells Meningeal carcinomatosis Ch. 13:287
Histiocytic disorders Ch. 14:326
Pattern 7 Destructive or necrotic processElements of the pattern: The brain biopsy specimen from a patient with known glioma shows extensive fibrinoid
parenchymal and vascular necrosis, consistent with radiation necrosis.
Additional Findings Diagnostic Considerations Chapter:page
Fibrinoid brain necrosis, vascular hyalinization, telangiectasias Radiation necrosis or treatment effects Ch. 19:417
Angionecrosis Radiation necrosis or treatment effects Ch. 19:417
Infection (toxoplasmosis) Ch. 21:476
Vasculitis Ch. 24:537
Vascular or perivascular inflammation Lymphoma (immunosuppressed host) Ch. 14:316
Severe demyelinating disease (rare) Ch. 22:485
Vasculitis Ch. 24:537
Intraluminal infiltrate Intravascular lymphoma Ch. 14:319
Granular vascular deposits CADASIL Ch. 24:546
Eosinophilic necrotic neurons Acute cerebral infarct Ch. 24:528
Neutrophil-rich infiltrate Infection (abscess) Ch. 21:478
Acute cerebral infract (rare) Ch. 24:528
Macrophage-rich infiltrate Severe demyelinating disease (rare) Ch. 22:485
Metabolic or toxic disorders Ch. 22:506, 510
Cerebral infarct Ch. 24:528
Granulomas or giant cells Infections (TB, fungal) Ch. 21:456
Vasculitis Ch. 24:537
Viral inclusions Encephalitis (HSV) Ch. 21:468
Pattern 8 Subtle pathology or near-normal biopsy specimenElements of the pattern: The brain biopsy specimen from a patient with chronic seizure disorder shows a nearly normal
cortex. However, there is a subtle disarray of the laminar architecture and clustering of large superficial neurons in the
center. Leptomeningeal gray matter heterotopia was also seen in other regions of the biopsy. This constellation of findings
is consistent with a malformation of cortical development (i.e., cortical dysplasia).Additional Findings Diagnostic Considerations Chapter:page
Reactive gliosis or cerebral edema Nonrepresentative biopsy Chs. 3–5
Subtle diffuse glioma Ch. 5:63
Hypothalamic hamartoma Ch. 7:146
Pineal cyst Ch. 8:157
Arachnoid cyst Ch. 13:309
Other developmental cyst Ch. 13:303
Metabolic or toxic disorders Ch. 22:506,
Nonanatomic cause of epilepsy 510
Subtle form of cortical dysplasia Ch. 23:515
Ch. 23:515
Glial atypia, clustering, or secondary structuring Diffuse glioma Ch. 5:63
Intraluminal atypical cells Intravascular lymphoma Ch. 14:319
Neuronal clustering and mild dysmorphism Hypothalamic hamartoma Ch. 7:146
Subtle form of cortical dysplasia Ch. 23:515
Balloon cells Focal cortical dysplasia, type IIb Ch. 23:518
Tuber Ch. 23:516,
Neuronal loss in hippocampus (CAI, CA4) Mesial temporal sclerosis/hippocampal sclerosis Ch. 23:520
Microglial nodules/scant perivascular Encephalitis (infectious, paraneoplastic) Ch. 21:469
inflammation Rasmussen encephalitis Ch. 23:523
Intravascular pigment Cerebral malaria Ch. 21:474
Red necrotic neurons Acute cerebral infarct Ch. 24:528
Vascular hyalinization Radiation effects Ch. 19:417
Meningioangiomatosis Ch. 20:433
Amyloid angiopathy Ch. 24:535
CADASIL Ch. 24:546
Arteriolosclerosis Ch. 24:533
Granular vascular deposits CADASIL Ch. 24:546
Hemorrhage/hemosiderin Epileptogenic “glial scar” Ch. 23:515
Amyloid angiopathy Ch. 24:535
Small cavernous angioma Ch. 24:545
Neurofibrillary tangles or neuritic plaques Alzheimer disease Ch. 25:553
Spongiform changes in gray matter Cerebral infarct Ch. 24:528
Creutzfeldt-Jakob disease (CJD) Ch. 25:566
Other neurodegenerative disorders (usually superficial Ch. 25:559
For additional histopathology algorithms, see “Minor Histopathologic Patterns of Nervous System Tumors” in the next chapter.


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Neuropathology Patterns and Introduction
Arie Perry,
Daniel J. Brat
Central Nervous System Tumor Classification Schemes and Additional “Neuropathology Patterns” 1
Electron Microscopy 1
Immunohistochemistry 11
Glial Markers 11
Neuronal Markers 11
Epithelial Markers 13
Proliferation Markers 13
Molecular Diagnostics 13
Central Nervous System Tumor Classification Schemes and Additional “Neuropathology
The rst comprehensive classi cation of nervous system tumors, formulated by Percival Bailey and Harvey Cushing in 1926, was founded
1on presumed parallels between embryologic and neoplastic cells. In large part, this histogenetic “cell of origin” model still forms the basis
for today’s nomenclature, although much of the terminology has changed considerably. Renewed interest in the role of developmental
2,3pathways in tumorigenesis has led to more recent studies focusing on cancer stem cells and progenitor cells. In 1949, however, as a
means of enhancing the clinical utility of tumor classi cation, Kernohan contributed a tumor-grading system focusing on correlations with
4patient prognosis. As progress was made over time, Russell and Rubinstein continued to modify and update the Bailey and Cushing
system from the 1960s through the 1980s. Nonetheless, considerable variability in diagnostic practice existed on both sides of the Atlantic.
In order to enhance consistency, an experts’ consensus scheme known as the World Health Organization (WHO) classi cation scheme was
5rst completed in 1979 and then revised in 1993, 2000, and 2007. This scheme is currently the most widely utilized by neuropathologists
for typing and grading tumors.
5The 2007 WHO “blue book” currently lists over 100 types of nervous system tumors and their variants. This level of complexity can be
daunting; therefore, an organized approach or algorithm is required. As a rst step, consideration of clinical and radiologic characteristics
is a critical way to narrow the di erential diagnosis, often to a few fairly common entities. In fact, the combination of patient age and
neuroimaging features (including tumor location) provides some of the most powerful diagnostic clues before any tissue is even sampled or
examined under the microscope. For example, the di erential varies considerably for supratentorial versus infratentorial, pediatric versus
adult, and enhancing versus nonenhancing tumors. The most common diagnostic considerations are summarized by age, location, and
imaging features in Table 1-1, with each speci c entity discussed in greater detail in subsequent chapters. Also, for a much more detailed
background on the use of neuroimaging, the reader is referred to Chapter 4. This is a particularly critical topic in surgical neuropathology,
since brain and spinal cord biopsy specimens are often small and the neuroimaging essentially provides the “gross pathology.”
Table 1-1
Common Central Nervous System Tumor Diagnoses by Location, Age, and Imaging Characteristics
Location Child/Young Adult Older Adult
Cerebral/supratentorial Ganglioglioma (TL, cyst-MEN, E) Grade II-III diffuse glioma
DNT (TL, intracortical nodules) (NE, focal E)
PNET (solid, E) GBM (E or rim E, “butterfly”
AT/RT (infant, E) mass)
Metastases (grey-white
junctions, E or rim E)
Lymphoma (periventricular,E)
Location Child/Young Adult Older Adult
Cerebellar/infratentorial/4th v. PA (cyst-MEN) Metastases (multiple, E or rim
Medulloblastoma (vermis, E) E)
Ependymoma (4th v., E) Hemangioblastoma
(cystChoroid plexus papilloma (4th v., E) MEN)
AT/RT (infant, E) Choroid plexus papilloma
(4th v., E)
Brainstem “Brainstem glioma” (pons, ± E) Gliomatosis cerebri
PA (dorsal, exophytic, cyst-MEN) (multifocal, ± E)
Spinal cord (intra-medullary) Ependymoma (E, ± syrinx) Ependymoma (E, ± syrinx)
PA (cystic, E) Diffuse astrocytoma
(illDrop metastases (cauda equina, E) defined, ± E)
MPE (filum terminale, E) MPE (filum terminale, E)
Paraganglioma (filum
terminale, E)
Spinal cord (intradural, Clear cell meningioma (± dural tail, E) Schwannoma (nerve origin,
extramedullary) Schwannoma (NF2, nerve origin, dumbbell shape, E) dumbbell shape, E)
Drop metastases (leptomeningeal, E) Meningioma (± dural tail, E)
Spinal cord (extradural) Bone tumor spread (EWS/PNET, usually E) Herniated disc (T1-spin echo
Meningioma (± dural tail, E) MRI, NE)
Abscess (E) Postoperative scar (E)
Vascular malformations (dilated vessels on imaging, ± E) Secondary lymphoma (E)
Metastases (E)
Abscess (E)
Extra-axial/dural Secondary lymphoma/leukemia (E) Meningioma (E with dural
Metastases (E)
lymphoma/leukemia (E)
Intrasellar Pituitary adenoma (solid, E) Pituitary adenoma (solid, E)
Craniopharyngioma (cystic, E) Craniopharyngioma (cystic, E
Rathke’s cleft cyst (cystic, ± E) Rathke’s cleft cyst (cystic, ±
Suprasellar/hypothalamic/optic Germinoma (solid, E) Colloid cyst (3rd v., ± E)
pathway/3rd v. Craniopharyngioma (cystic, E) Craniopharyngioma (cystic,
PA (cyst-MEN) E)
Pilomyxoid astrocytoma (infant, solid, E)
Pineal Germinoma (solid, E)Pineocytoma (solid, E)Pineoblastoma (solid, Pineocytoma (solid, E)Pineal
E)Pineal cyst (cystic, NE) cyst (cystic, NE)
Thalamus PA (cyst-MEN) AA/GBM (E or rim E)
AA/GBM (E or rim E) Lymphoma (E, ±
Cerebellopontine angle Vestibular schwannoma (NF2, E, involves internal auditory Vestibular schwannoma (E,
meatus) involves internal auditory
Choroid plexus tumor (E, component in 4th v.) meatus)
Meningioma (E with dural
Lateral ventricle Central neurocytoma (E)SEGA (tuberous sclerosis, E)Choroid Central neurocytoma (E)
plexus papilloma (E)Choroid plexus carcinoma (infant, E, SEGA (tuberous sclerosis, E)
large, invasive) Choroid plexus papilloma (E)
Subependymoma (± E)
Meningioma (E with dural
Nerve root/paraspinal Neurofibroma (NF1, E) Schwannoma (E, dumbbell
MPNST (NF1, E, necrotic) shape)
Meningioma (E with dural
Secondary lymphoma (E)

Neurofibroma (NF1, E))
Location Child/Young Adult Older Adult
MPNST (E, necrotic)
AA, anaplastic astrocytoma; AT/RT, atypical teratoid/rhabdoid tumor; DNT, dysembryoplastic neuroepithelial tumor; E, enhancing; EWS,
Ewing’s sarcoma; 4th v., fourth ventricle; GBM, glioblastoma; MEN, mural enhancing nodule; MPE, myxopapillary ependymoma; MPNST,
malignant peripheral nerve sheath tumor; MRI, magnetic resonance imaging; NE, nonenhancing; NF, neurofibroma; NF1, neurofibromatosis
type 1; PA, pilocytic astrocytoma; PNET, primitive neuroectodermal tumor; SEGA, subependymal giant cell astrocytoma; 3rd v., third
ventricle; TL, temporal lobe.
The next set of clues is naturally provided by histopathology. The eight major patterns provided at the beginning of this textbook narrow
the di erential diagnosis considerably based purely on the overall low-magni cation appearance, and the subheadings of additional
ndings provides a useful diagnostic algorithm. When presented with a challenging biopsy specimen, the pathologist can start with either
the clinical or morphology-based approaches but is encouraged to incorporate all available data before making a nal diagnosis. In the
vast majority of cases, the clinical, radiologic, and pathologic features are all consistent with one another; if not, the pathologist should
carefully reexamine the specimen to be sure that all appropriate possibilities have been considered and if necessary, excluded with
ancillary studies. The use of common ancillary diagnostic techniques is brieHy summarized in this chapter, with many more examples
provided in the subsequent topic-speci c chapters. As useful secondary algorithms, the major di erential diagnosis based on an additional
2 0 minor histologic patterns is presented in Table 1-2, with helpful clinicopathologic features summarized for 21 common di erential
diagnoses in Table 1-3.
Table 1-2
Minor Histopathologic Patterns of Nervous System Tumors
“Fried Egg” or Clear Cells Lobulated, Nested, or Nodular
• Oligodendroglioma • Desmoplastic/nodular medulloblastoma
• Glioblastoma, small cell variant • Extensively nodular medulloblastoma
• Dysembryoplastic neuroepithelial tumor • Dysembryoplastic neuroepithelial tumor
• Clear cell ependymoma • Oligodendrogliomas, mostly high-grade
• Central/extraventricular neurocytoma • Subependymoma
• Pineocytoma • Ganglioglioma
• Pilocytic astrocytoma • Paraganglioma
• Poorly preserved diffuse astrocytomas • Metastatic carcinoma
• Autolyzed non-neoplastic brain • Pineal parenchymal tumors, mostly of intermediate
• Demyelinating disease (macrophages) differentiation
• Cerebral infarct (macrophages) • Plexiform neurofibroma or schwannoma
• Rosette-forming glioneuronal tumor • Epithelioid MPNST
• Paraganglioma • Meningiomas: mostly meningothelial, chordoid, and atypical
• Clear cell meningioma • Melanocytoma and melanoma
• Germinoma • Germinoma
• Pituitary adenoma • Pituitary adenomaFascicles/Storiform Bundles of Spindled Cells Sheets of Epithelioid Cells
• Fibrous, transitional, or anaplastic meningiomas • Metastatic carcinoma
• Schwannoma • Meningioma
• Solitary fibrous tumor • Melanoma
• Hemangiopericytoma • Atypical teratoid/rhabdoid tumor
• MPNST or other spindle cell sarcomas • Pituitary adenoma
• Spindled glioblastomas/astrocytomas • Anaplastic oligodendroglioma
• Gliosarcoma • Ependymoma
• Pleomorphic xanthoastrocytoma • Choroid plexus tumors
• Desmoplastic gangliolioma/astrocytoma • Astroblastoma
• Tanycytic ependymoma • Chordoid glioma
• Atypical teratoid/rhabdoid tumor • Germ cell tumors
• Melanocytoma or melanoma • Paraganglioma
• Pituicytoma • Epithelioid glioblastoma
• Spindle cell oncocytoma of pituitary • Epithelioid nerve sheath tumors
• Histiocytic disorders • Craniopharyngioma
• Fibrous or granulomatous reactions • Anaplastic large cell lymphoma
• Plasmacytoma
Monomorphic Cytology Biphasic Pattern (Loose and Compact Areas)
• Central/extraventricular neurocytomas • Pilocytic astrocytoma
• Pineocytoma • Pleomorphic xanthoastrocytoma
• Oligodendroglioma • Ganglioglioma• Pituitary adenoma • Schwannoma
• Pilomyxoid astrocytoma • Hemangiopericytoma
• Angiocentric glioma • Malignant peripheral nerve sheath tumor
Microcystic Myxoid/Mucin-rich
• Diffuse gliomas, mostly low-grade • Dysembryoplastic neuroepithelial tumor
• Pilocytic astrocytomas • Myxopapillary ependymoma
• Pleomorphic xanthoastrocytoma • Chordoid glioma
• Subependymoma • Chordoid meningioma
• Ganglioglioma • Metaplastic chondromyxoid meningioma
• Schwannoma • Pilocytic/pilomyxoid astrocytomas
• Microcystic meningioma • Diffuse gliomas, mostly low-grade
• Hemangioblastoma • Rosette-forming glioneuronal tumor
• Yolk sac tumor • Atypical teratoid/rhabdoid tumor
• Teratoma • Nerve sheath tumors
• Craniopharyngioma • Yolk sac tumor
• Teratoma
Rosette Forming Perivascular Pseudorosettes
• Ependymoma (true ependymal) • Ependymoma
• Medulloblastoma (Homer Wright) • Astroblastoma
• CNS PNET (Homer Wright, ependymoblastic) • Angiocentric glioma
• Neurocytomas (neurocytic) • Papillary glioneuronal tumor
• Pineocytoma (pineocytic) • Central/extraventricular neurocytomas
• Pineoblastoma (pineoblastic) • Medulloblastomas/PNETs (occasionally)
• Embryonal tumor with abundant neuropil and true rosettes • Glioblastoma (occasionally)
(ependymoblastic) • Papillary meningioma
• Pituitary adenoma (rosette-like pattern) • Pituitary adenomaPalisading/Pseudopalisading Cells Papillary/Pseudopapillary
• Glioblastoma (pseudopalisading necrosis) • Choroid plexus tumors
• Schwannoma (Verocay bodies) • Papillary ependymoma
• Pilocytic astrocytoma (spongioblastic) • Astroblastoma
• Oligodendroglioma (spongioblastic) • Papillary meningioma
• Ependymoma (spongioblastic) • Hemangiopericytoma
• Medulloblastoma/PNET (spongioblastic) • Papillary glioneuronal tumor
• Angiocentric glioma (subpial palisades) • Atypical teratoid/rhabdoid tumor
• Papillary craniopharyngioma
• Germ cell tumors (e.g., yolk sac tumor)
• Papillary tumor of the pineal region
“Small Blue Cells” (i.e., Primitive) Multinucleated Giant Cells
• Medulloblastoma • Giant cell glioblastoma
• CNS PNET • Pleomorphic xanthoastrocytoma
• Pineoblastoma • Subependymal giant cell astrocytoma
• Atypical teratoid/rhabdoid tumor • Melanoma
• Lymphoma/leukemia • Choriocarcinoma
• Glioblastoma, PNET-like variant • Giant cell ependymoma
• Choroid plexus carcinoma • “Ancient changes” in schwannoma, neurofibroma, or
• Ewing’s sarcoma/PNET meningioma
• Hemangiopericytoma • Pilocytic astrocytoma (occasionally)
• Malignant peripheral nerve sheath tumor (occasionally) • Ganglioglioma (occasionally)
• Melanoma (occasionally) • Any poorly differentiated malignancyExtensive Calcification Desmoplasia or Sclerosis
• Ganglioglioma • Astroblastoma
• Central/extraventricular neurocytomas • Desmoplastic/nodular medulloblastoma
• Oligodendroglioma • Desmoplastic infantile ganglioglioma/astrocytoma
• Psammomatous meningioma • Meningioma, especially clear cell variant
• Meningioangiomatosis • Solitary fibrous tumor
• Calcifying pseudoneoplasm of the neuroaxis • Hemangiopericytoma or other sarcomas
• Craniopharyngioma • Neurofibroma
• Tuber/focal cortical dysplasia • Pleomorphic xanthoastrocytoma
• Vascular malformation • Gliosarcoma
• Subependymoma (occasionally) • Ganglioglioma
• Ependymoma (occasionally) • Ependymoma (occasionally)
• Astroblastoma (occasionally) • Abscess
• Choroid plexus papilloma (occasionally) • Granulomas
• Meningeal inflammation or neoplasm
Hypervascular Inflammation-rich
• Hemangioblastoma • Ganglioglioma
• Hemangiomas/vascular malformations • Pleomorphic xanthoastrocytoma
• Vascular neoplasms (e.g., angiosarcoma) • Gemistocytic astrocytoma
• Hemangiopericytoma • Germinoma
• Angiomatous meningioma • Chordoid glioma
• Glioblastomas/high-grade gliomas • Lymphoplasmacyte-rich meningioma
• Pilocytic astrocytoma (occasionally) • Inflammatory myofibroblastic tumor
• Lymphomas and histiocytic disorders
• Demyelinating diseases
• Infections, granulomas, collagen vascular disordersRosenthal Fibers/Eosinophilic Granular Bodies Discohesive
• Pilocytic astrocytoma • Atypical teratoid/rhabdoid tumor
• Ganglioglioma • Papillary and/or rhabdoid meningiomas
• Pleomorphic xanthoastrocytoma • Lymphomas/leukemias
• Dysembryoplastic neuroepithelial tumor (occasionally) • Histiocytic disorders
• Piloid gliosis next to craniopharyngioma, hemangioblastoma, • Poorly differentiated malignancies
ependymoma, pineal cyst, or any slowly progressive process
CNS, central nervous system; PNET, primitive neuroectodermal tumor.
Table 1-3
Helpful Features in Common Differential Diagnoses of Surgical Neuropathology
Atypical Gliosis vs. Diffuse Glioma (WHO Grade II)
• Evenly spaced astrocytes • Clustered cells
• Abundant eosinophilic cytoplasm • “Naked nuclei”
• Radially oriented GFAP+ processes • Large, hyperchromatic, irregular nuclei
• Other reactive changes, such as • Ki-67 labels suspicious nuclei
inflammatory infiltrates, macrophages, • Nuclei are strongly p53+ (not helpful if negative)
hemosiderin deposits, etc. • WT1+ processes
• Demonstrable chromosomal alternations
Diffuse Astrocytoma vs. Pilocytic Astrocytoma
• MRI: Ill-defined, nonenhancing • MRI: Demarcated, cystic, enhancing
• Predominantly infiltrative • Predominantly solid with focal invasion
• Clustered cells • Biphasic loose and compact areas
• “Naked nuclei” • Long, thin, “hairlike” processes
• Large, hyperchromatic, irregular nuclei • Rosenthal fibers and EGBs
• Nuclei are strongly p53+ (not helpful if • Multinucleate “pennies on a plate” cells
negative) • Hyalinized blood vessels
• Numerous intratumoral NFP+ axons • Strong, diffusely GFAP+
• Few intratumoral NFP+ axons
• Low Ki-67 labeling index, except in blood vessels
Pleomorphic Xanthoastrocytoma vs. Giant Cell Glioblastoma
• MRI: Demarcated, cystic, enhancing, often • MRI: Ring-enhancing, marked edema and mass effects
temporal lobe, minimal edema • “Frankly anaplastic” cytology
• Rare mitoses, despite pleomorphism • Numerous mitoses
• Spindled mesenchymal-like element • Atypical mitoses
• Foamy tumor cells (only in ~30%) • Pseudopalisading necrosis
• Eosinophilic granular bodies • Extensively p53+
• CD34+ cells
Diffuse Glioma/Glioblastoma vs. CNS Lymphoma
• Secondary structures, such as perineuronal • Angiocentric growth pattern
satellitosis • Discohesive on intraoperative smear
• “Naked nuclei” or fibrillary processes • Open chromatin, large nucleoli
• Eosinophilic cytoplasm • Rounded cells with scant blue cytoplasm
• Nuclear hyperchromasia/pleomorphism • Prominent apoptosis
• Microvascular proliferation • LCA or CD20+
• Pseudopalisading necrosis • Intermixed reactive T lymphocytes
• GFAP or S-100 + or both
High-grade Glioma or Lymphoma vs. Demyelinating Disease
• Frankly anaplastic cells • Relatively sharp demarcation
• Ill-defined lesional borders • Fairly restricted to white matter
• Perineuronal satellitosis (gliomas) • Myelin pallor with hypercellular infiltrate
• Necrosis (gliomas or immunodeficiency- • Sheets of CD68+ histiocytes (better recognized on smear than frozen section)
associated lymphomas) • Creutzfeldt cells
• Microvascular proliferation (gliomas) • LFB-PAS shows marked myelin loss
• GFAP+ or CD20+ atypical cells • NFP shows relative axonal preservation
• EBV+ cells (immunodeficiency-associated • CD20+ cells are all small and maturelymphomas) • GFAP+ cells are evenly spaced
Glioblastoma vs. Abscess
• Pseudopalisading necrosis • Abundant neutrophils in necrotic foci
• Microvascular proliferation • “Tissue culture” fibroblasts with variable nuclear atypia
• Infiltrative component • Inflammatory rim
• Secondary structure formation • Brisk gliosis at edge of lesion
• GFAP+ atypical cells • Trichrome reveals collagen deposition
• Strongly p53+
• WT1+ processes
Glioblastoma vs. Metastasis
• Infiltrative growth pattern • Sharp demarcation from brain
• Secondary structure formation • Glands or cytoplasmic mucin (adenoca)
• Pseudopalisading necrosis • Azzopardi effect (small cell ca)
• Microvascular proliferation • Pigment (melanoma)
• GFAP+ • Hemorrhage (lung ca, melanoma, renal cell ca, choriocarcinoma)
• NFP+ intratumoral axons • CK7+, TTF1+ (lung ca)
• Cytokeratin CAM 5.2- (Do not use • CK20+, CDX2+ (colon ca)
cocktails such as AE1/AE3, which often
• CK7+, mammaglobin+ (breast ca)
cross-react with GFAP) • CD10+ (renal cell ca)
• HMB45+, Melan-A+ (melanoma)
Recurrence/Progression of Glioma vs. Radiation Necrosis/Radiation Effects
• Pseudopalisading necrosis • Coagulative and fibrinoid parenchymal and vascular necrosis
• Microvascular proliferation • Vascular hyalinization
• Viable tumor with mitotic activity • Vascular telangiectasias
• High Ki-67 labeling index • Rarefied hypocellular parenchyma
• Dystrophic calcification
• Radiation-induced atypia (bizarre bubbly nuclei and abundant pink cytoplasm)
Anaplastic Oligodendroglioma vs. Small Cell Glioblastoma
• Round uniform nuclei • Oval uniform nuclei
• Enlarged epithelioid cells with open • Frequent mitoses despite “low-grade” cytology (delicate chromatin)
chromatin and large nucleoli • Pseudopalisading necrosis
• Mucin-rich microcystic spaces • GFAP+ thin cytoplasmic processes
• GFAP+ minigemistocytes and • EGFRvIII expression (~50%)
gliofibrillary oligodendrocytes • EGFR amplification (~70%)
• Chromosome 1p/19q codeletions • Chromosome 10q deletions (>95%)
Oligodendroglioma vs. Diffuse Astrocytoma
• Round uniform nuclei with crisp nuclear • Variably elongate, irregular, hyperchromatic nuclei
membranes and small nucleoli • “Naked nuclei,” elongate processes, or large eccentric belly of pink cytoplasm
• Clear haloes, no cytoplasm, or small (gemistocytes)
eccentric belly of pink cytoplasm (mini- or • Variably GFAP+ cytoplasm in most, although fibrillary and small cell variants
microgemistocytes) may be negative due to minimal cytoplasm; high GFAP background makes
• “Chicken wire” capillaries interpretation difficult in others
• Hypercellular nodules • Strongly p53+ (50%-60%)
• Epithelioid/plasmacytoid cells with large
nucleoli (anaplastic)
• GFAP- or GFAP+ minigemistocytes and
gliofibrillary oligodendrocytes
• Mostly
p53• Chromosome 1p/19q codeletion
Oligodendroglioma vs. Dysembryoplastic Neuroepithelial Tumor
• MRI: Cerebral nonenhancing tumor with • MRI: Gyriform, intracortical lesion, often mesial temporal lobe, with minimal mass
significant mass effect effect; focal enhancement in a subset
• Extensive white matter component • Mucin-rich, patterned intracortical nodules
• Perineuronal satellitosis prominent • “Floating neurons”
• Chromosome 1p/19q codeletion • Component resembling pilocytic astrocytoma in complex form
• Adjacent cortical dysplasia
• Rosenthal fibers/EGBs (occasionally)
Oligodendroglioma vs. Central/Extraventricular Neurocytoma• Ill-defined margins • Solid tumor with discrete borders
• Perineuronal satellitosis • Neurocytic rosettes/neuropil formation
• GFAP+ minigemistocytes and • Diffusely synaptophysin+, including center of neurocytic rosettes
gliofibrillary oligodendrocytes • Neuronal features on EM
• Entrapped NFP+ axons
• Chromosome 1p/19q codeletion
Oligodendroglioma vs. Clear Cell Ependymoma
• Ill-defined margins • Sharp demarcation
• Perineuronal satellitosis • Vague perivascular pseudorosettes, highlighted on GFAP stain
• GFAP+ minigemistocytes and • Nuclear grooves/folds
gliofibrillary oligodendrocytes • Dot-like cytoplasmic EMA+
• Entrapped NFP+ axons • NFP+ axons pushed to periphery of tumor
• Chromosome 1p/19q codeletion • Ependymal features on EM
Ependymoma vs. Diffuse Astrocytoma
• Sharp demarcation • Infiltrative growth pattern
• Perivascular pseudorosettes, highlighted • Secondary structures
on GFAP stain • “Naked nuclei”
• Dot-like cytoplasmically EMA+ • Numerous intratumoral NFP+ axons
• NFP+ axons pushed to periphery of tumor
• Ependymal features on EM
Cellular Ependymoma vs. Medulloblastoma/PNET
• Solid growth pattern • Solid and infiltrative growth patterns
• Low mitotic/proliferative • High mitotic/proliferative index
• Perivascular pseudorosettes with fibrillar • Homer Wright rosettes and occasional pseudorosettes with delicate neuropil
processes, highlighted with GFAP • Synaptophysin positive
• Dot-like cytoplasmically EMA+ • Ki-67 high
• NFP+ axons pushed to the periphery
Medulloblastoma/PNET vs. Atypical Teratoid/Rhabdoid Tumor
• Mostly children/young adults • Mostly infants (
• Solid and infiltrative growth patterns
• Homer Wright rosettes
• Retained INI1 expression
• Synaptophysin+, GFAP focal+, most
other markers negative
• Genetics often shows i17q and/or MYC
amplifications in anaplastic/large cell
Normal Brain Histopathology
Daniel J. Brat
Cell Types  15
Neurons  15
Glia  17
Astrocytes  17
Oligodendrocytes  20
Ependyma  20
Choroid Plexus  20
Microglia  20
Blood Vessels  21
Meningothelial Cells  21
Melanocytes  22
Tissue Organization  22
Cerebral Cortex  22
White Matter  23
Basal Ganglia  23
Thalamus  24
Hippocampus  24
Pineal Gland  25
Pituitary Gland  26
Cerebellum  26
Brainstem  28
Midbrain  28
Pons  28
Medulla  29
Spinal Cord  29
Meninges  29
Peripheral Nerve, Schwann Cells, and Dorsal Root Ganglia  29
Features of Infancy and Childhood  31
Features of the Aging Nervous System  31
The practice of surgical neuropathology can be challenging for the generalist and specialist
alike. Much of this di culty results from the intrinsic complexity of the human central nervous
system (CNS), an organ that is unrivaled in regional variation and specialized organization.#
Nevertheless, a basic understanding of the normal cellular and tissue organization of the brain is
absolutely necessary for the practice of surgical neuropathology, since recognition of the
abnormal rests on a rm knowledge of the normal. Even in the current age of advanced
neuroimaging and image-guided biopsies, many neurosurgically sampled specimens contain
normal or only slightly abnormal tissue that needs to be recognized as nondiagnostic. Indeed,
much of the anxiety that arises at the time of frozen section seems to be due to a discomfort with
distinguishing normal from abnormal rather than from correctly categorizing an abnormal
biopsy specimen. The “sea of pink” noted under the microscope from a brain biopsy of normal
brain tissue has been known to cause even the most experienced surgical pathologist a great
degree of uncertainty. The changes of “reactive gliosis” only exacerbate the problem. Much like
the pattern recognition approach used in this textbook for classifying diseases of the CNS, so too
can the normal histology of the brain be approached based on recognition of tissue patterns. Like
other forms of pattern recognition, this takes practice. For the neuropathologist, repeated
exposure to normal CNS structure occurs from the regular review of autopsied brains. For
generalists that practice surgical neuropathology, review of autopsied brain sections can add
con dence in the recognition of normal CNS tissue patterns. This chapter introduces the cell
types and normal histology of the human CNS at a depth necessary for routine diagnostic
practice. Most of its content describes the normal adult brain, but certain aspects of age-related
phenomena and developmental features that are routinely encountered in diagnostic
neuropathology are also considered.
Cell Types
Given the high degree of functional complexity, it may be surprising that the brain parenchyma
consists predominantly of only two cell types, neurons and glia. Both are large families with
many members that have highly specialized functions, yet the underlying structure and cell
biology of each retain some central features. Most challenging for the practicing surgical
pathologist is the great degree of morphologic and geographic diversity of normal, reactive, and
degenerative states of these two cell families.
Neurons are the integrating and transmitting cells of the nervous system, communicating by
chemical and electrical means. The spectrum of their morphology, connectivity, and function is
enormous. As a rule, neurons have a cell body, branching processes called dendrites for
integrating incoming signals, and a longer cell process—the axon—with a terminal synapse for
chemically transmitting an electric signal over a short distance from one neuron to the next (or
to a muscle cell through a neuromuscular junction). Cell body shape and size, as well as the
number and arrangement of branching processes, vary considerably. For practicing pathologists,
recognizing the major forms of neurons within their anatomic setting is crucial, since individual
populations show di1erential vulnerability to injury and variable pathologic reactions in speci c
disease processes.
The pyramidal neurons of the cerebral cortex and sub elds of the hippocampus represent a
morphologic prototype (Fig. 2-1A and B). They are characterized by large, triangular cell bodies,
a prominent apical dendrite extending toward the brain’s surface, and numerous ner branching
basal dendrites. Measuring approximately 10 to 50 μm in greatest dimension, their cell bodies
contain abundant cytoplasm, variable hematoxiphilic Nissl substance (rough endoplasmic
reticulum) near the entry zone to processes, and a large nucleus with open chromatin and aprominent nucleolus (open chromatin and prominent nucleoli are typical of neurons and
distinguish them from resting glia).FIGURE 2-1 Neurons. A, Pyramidal neurons (arrow) of the cerebral cortex.
B, Pyramidal neurons of the hippocampus. C, Betz cells (upper motor
neurons) of the motor cortex (arrow). D, Granular neurons of the dentate
fascia of the hippocampal formation. E, Purkinje cells (arrow) and granular
cells (arrowhead) of the cerebellar cortex. F, Anterior horn cells (lower motor
neurons) of the spinal cord. G, Dopaminergic neurons of the substantia nigra
are deeply pigmented due to accumulation of neuromelanin.
Cortical granular (stellate) neurons are the smaller counterparts of pyramidal neurons in the
cortex, typically measuring 15 μm or less in diameter. Being interneurons, they have numerous
shorter processes that remain within the confines of the cortex.
Betz cells are the largest neurons of the cerebral cortex (70 to 100 μm) and are found in the
primary motor cortex where they dwarf their neighboring cortical pyramidal cells (Fig. 2-1C).
The amounts of cytoplasm and Nissl substance and the number of visible processes far exceed
normal pyramidal cells. Betz cells are upper motor neurons.
Small, tightly packed granular neurons form the stratum granulosum of the dentate gyrus in the
medial temporal lobe, intimately connected to the hippocampus proper (Fig. 2-1D). These
neurons are nearly as small as cerebellar granular cells and have an extensive dendritic arbor
that forms the adjacent molecular layer of the dentate gyrus.
Purkinje cells are large (50–80 μm), histologically distinctive neurons of the cerebellum with
cell bodies that sit at the interface of the molecular and internal granular cell layers (Fig. 2-1E).
Each neuron has a prominent pink cell body and an expansive dendritic tree with thick processes
that extend into the molecular layer, as well as a large axon that travels centrally out of the
cerebellar cortex.
Granular neurons of the cerebellar granular cell layer are tiny and densely packed, often
displaying a linear arrangement or loose rosettes around delicate neuropil (see Fig. 2-1E).
Perinuclear cytoplasm is sparse, giving the appearance of only nuclei on hematoxylin and eosin
(H&E) stains. This population can cause confusion on frozen section or cytologic preparations#
because they resemble “small round blue-cell tumors.”
Anterior horn cells are large, lower motor neurons (alpha motor neurons) that populate all
levels of the spinal cord in the anterior horns and send long axonal processes via the anterior
roots for their eventual termination on peripheral skeletal muscle endplates (Fig. 2-1F).
The CNS also contains a small number of highly specialized nuclei that contain neurons that
produce speci c bioaminergic neurotransmitters and project di1usely throughout the brain to
a1ect global or regional tone. Rarely seen in biopsied material, these include the substantia
nigra, locus ceruleus, raphe nuclei, and nucleus basalis of Meynert. The dopaminergic cells of the
substantia nigra pars compacta (and the ventral tegmental area) are large, heavily pigmented
neurons with “neuromelanin” (not to be confused with melanin of melanocytes), which
accumulates in the cytoplasm as coarse brown granules and represents a combination of oxidized
and polymerized dopamine within lysosomal granules (Fig. 2-1G; selectively vulnerable in
Parkinson disease). Similarly, the locus ceruleus, located near the fourth ventricle in the rostral
pontine tegmentum, contains a population of large, pigmented neurons that serve as a major
source of norepinephrine in the brain (selectively vulnerable in Parkinson disease). Neurons
located in the raphe nuclei, located along the midline of the brainstem, are similar in size and
shape to the noradrenergic neurons of the locus ceruleus, but lack the pigmentation. These cells
produce serotonin and have di1use projections throughout the nervous system, but most heavily
innervate limbic and sensory regions. Within the basal forebrain, inferior to the anterior
commisure in a region called the substantia innominata, is the nucleus basalis of Meynert, a
collection of large cholinergic neurons that project throughout the cerebral cortex (selectively
vulnerable in Alzheimer disease).
Glia account for approximately 90% of all CNS cells and have been generally regarded as “glue,”
providing structural and functional support for neuronal elements. In fact, they are functionally
much more diverse and biologically important than originally suspected, such that
neurobiologists have shifted away from this overly “neuronocentric” perspective. Glia are divided
into the macroglia or true glia—astrocytes, oligodendrocytes, and ependyma—and the microglia,
which are actually of hematopoietic rather than true glial derivation.
Astrocytes are the multipolar, “starlike” glial cells of the CNS (Figs. 2-2 and 2-3). They can be
subdivided into protoplasmic and brillary families based on their location and morphology.
Protoplasmic astrocytes reside in the cortex, whereas brillary astrocytes populate the white matter.
In addition to similar cell shapes and numerous processes, all astrocytes contain abundant
cytoplasmic intermediate laments, largely composed of glial brillary acidic protein (GFAP). In
the resting state, astrocyte nuclei are recognized on H&E-stained sections, but the scant, delicate
cytoplasm and processes are not readily seen since they blend with surrounding neuropil. Nuclei
are oblong with a chromatin pattern that is lighter and looser than either oligodendrocytes or
neoplastic astrocytes (Fig. 2-2A). Nucleoli are not present in most resting astrocytes, in contrast
to neurons. Many astrocytes have processes that terminate as end-feet on blood vessel walls,
where they contribute to the blood–brain barrier. Others have processes that extend end-feet to the
pial surface of the brain, contributing to the glia limitans of the brain–cerebrospinal uid (CSF)
barrier.FIGURE 2-2 Normal glia. A, Normal white matter shows oligodendrocytes
(arrow), which have round dark nuclei often with a slight perinuclear halo,
and astrocytes, with oblong nuclei (arrowheads). Glial cytoplasm blends with
the neuropil and cannot typically be noted in the resting state. B, Cytologic
preparation of normal cortex demonstrates normal oligodendrocytes (short
arrow), astrocytes (arrowhead), neuron (long arrow), and capillaries
(asterisk).FIGURE 2-3 Reactive glia. A, B, Gemistocytic astrocytes (arrows) are one
form of reactive change in which the astrocytic cytoplasm is distended and
esosinophilic processes are readily identified.C, Immunohistochemistry for
GFAP highlights reactive astrocytes and emphasizes their “starlike” quality.
D, E, Piloid gliosis is a highly fibrillar form of reactive gliosis that is composed
of dense, elongate astrocytic processes that are tightly packed together and
are often associated with numerous Rosenthal fibers. In this case, piloid
gliosis forms the wall of a pineal cyst. F, Alzheimer type II astrocytes (arrow)
have enlarged, clear nuclei and are seen in states of hyperammonemia. G,
Bergmann gliosis occurs at the interface of the molecular and granular layers
of the cerebellum, generally in response to Purkinje cell injury. In this case, a
nearly normal complement of Purkinje cells (arrow) is seen on the right,
whereas Purkinje cells have been replaced by one to three layers of
Bergmann glia containing oval nuclei with long coarse cytoplasmic processes
radiating toward the pial surface (left side). The patient was an infant as
evidenced by the thin remnant of the external granular layer. H, Creutzfeldt
cells (granular mitoses) are reactive cells with fragmented nuclear material
(arrow) that can be mistaken for mitotic figures.
Astrocytes are activated in response to a variety of pathologic conditions (Fig. 2-3). The
morphologic spectrum of reactive astrocytosis is critical to recognize because (1) it focuses#
attention on pathologically a1ected regions for further evaluation; (2) it validates the
assumption that a disease process is present in the CNS (i.e., rather than artifact); and (3)
reactive astrocytosis often causes diagnostic dilemmas due to its morphologic similarity to
neoplastic conditions. Reactive astrocytosis involves both proliferation and hypertrophy of
astrocytes, and its appearance varies with the chronicity and severity of the insult. The initial
response is enlargement of cell body, processes, nuclei, and nucleoli. In H&E-stained sections, the
presence of visible astrocytic cytoplasm and processes is almost always a pathologic nding (Fig.
2-3B). Immunohistochemistry for GFAP highlights the reactive nature of these astrocytes,
demonstrating the extensive arborizing of their processes and the orientation of the reactive cells
to the underlying injury (Fig. 2-3C). Reactive astrocytes of longer duration often take on a
gemistocytic (from the Greek word gemistos, meaning “stu1ed”) appearance, with large amounts
of brightly eosinophilic cytoplasm in their eccentrically placed cell bodies (Fig. 2-3A). The
relatively even spacing of these astrocytes and radially arranged processes help to distinguish
them as reactive, rather than neoplastic.
Chronic reactive astrocytosis that occurs around a slowly growing lesion is often more brillar in
nature, with numerous long astrocytic processes forming a layer of dense gliosis adjacent to
injury. Rosenthal bers are large, Eame-shaped or globular proteinaceous deposits that may be
seen in this type of long-standing process; when present, this form of reaction is often termed
piloid gliosis, due to its morphologic overlap with the compact regions of pilocytic astrocytoma
(Fig. 2-3D and E). It is most often encountered adjacent to slow-growing neoplasms (e.g.,
craniopharyngioma, ependymoma, hemangioblastoma) and benign cystic lesions (e.g., pineal
cyst, spinal syrinx).
Alzheimer type II astrocytes are a reactive form seen in states of elevated blood ammonia,
usually related to renal or hepatic disease (Fig. 2-3F). They are present in highest concentration
in the basal ganglia where cells show nuclear swelling, marked chromatin clearing, and
micronucleoli. Cytoplasmic hypertrophy is not prominent in this form of astrocytosis, and
usually, the nuclei have no appreciable cytoplasm.
Bergmann glia are specialized astrocytes located between the molecular and granular layers of
the cerebellum. Cells are only one to two layers thick and can go unnoticed in resting states. In
response to cerebellar injury, especially to individual Purkinje cell loss from ischemia or hypoxia,
the reactive proliferation of this cell layer is referred to as Bergmann gliosis. On H&E sections, the
Purkinje cells are replaced with one to three layers of oval nuclei associated with coarse
GFAPpositive fibrillary processes radiating toward the pia (Fig. 2-3G).
Creutzfeldt cells are another form of reactive astrocytes that have abundant cytoplasm and
“granular mitoses,” the fragmenting of nuclear material that gives the impression of multiple
micronuclei (Fig. 2-3H). They are not speci c, but are seen most often in active inEammatory
diseases (classic in demyelinating disease). It is important not to mistake them for the mitoses of
an infiltrating astrocytoma.
Markedly enlarged and cytologically atypical astrocytes can be seen in many non-neoplastic
conditions, although the nuclear atypia is often most pronounced in reactions to radiation
(radiation atypia; see Chapter 20) and progressive multifocal leukoencephalopathy (PML; see Chapter
22). In both conditions, nuclei can be bizarre with marked hyperchromasia, multilobation, and
irregular outlines. The context of additional microscopic changes and the clinical history are
often required to avoid a misdiagnosis of neoplasm.
Oligodendrocytes are the myelinating cells of the CNS and are therefore more numerous in white
than in gray matter (see Fig. 2-2). With their thin, short, cellular processes extending in all
directions, oligodendrocytes provide internodes of myelination to multiple axonal processes in
their environment. In H&E-stained sections, only the nucleus of oligodendrocytes is usually
visible due to the blending of cellular processes with the neuropil. A clear zone surrounding the
nucleus, the so-called perinuclear halo, often highlights oligodendrocytes as well as tumors with
similar cytologic features (i.e., oligodendrogliomas); in either case, this appears due to a
retraction artifact of formalin xation. Nuclei are generally round and regular, but vary from small
and darkly basophilic (accounting for a majority) to slightly larger with pale vesicular nuclei.
Nucleoli are not usually noted by standard light microscopy. In the white matter,
oligodendrocytes are disposed along the length of axonal processes, whereas in the cerebral
cortex, they are scattered within the neuropil and concentrated immediately surrounding
neuronal cell bodies (satellite cells). In the latter location, they may serve as a progenitor
Ependyma are cuboidal to columnar epithelioid glial cells that form a single-layered covering of
the ventricular system (Fig. 2-4). On their ventricular (apical) surface, ependyma have
microscopically visible cilia and microvilli, whereas their lateral surfaces are tethered to one
another by desmosomes, forming a functional CSF–brain barrier. Ependymal cytoplasm is pale to
eosinophilic, and nuclei are oval and hyperchromatic. Within the supra- and infratentorial
compartments, ependyma are fairly homogeneous, varying slightly by anatomic location in their
cell height and degree of ciliation (Fig. 2-4C and D). Within the spine, the central canal is lined
by ependyma and serves as a conduit for CSF during childhood. In adulthood, the central canal is
collapsed and vestigial, remaining only as a central collection of clustered ependyma throughout
the spinal cord length (Fig. 2-4E). Along the lateral ventricles, especially posteriorly, it is fairly
common to encounter either entrapped outpouchings of ependyma or small clusters forming
canals (Fig. 2-4F). These do not represent hamartomas or malformations, but only clinically
inconsequential remnants of imperfect development.FIGURE 2-4 Choroid plexus and ependyma. A, B, Choroid plexus
(arrowhead) is a tufted aggregate of vascular channels lined by a single layer
of choroid epithelium, which contains large pink cells with a cobblestone-like
surface. Choroid plexus extends from its entry zone in the lateral ventricle,
where it transitions from the ependymal lining (arrow). C, D, Ependyma are a
single layer of cuboidal to columnar epithelioid glial cells that line the
ventricular system and form the brain–CSF barrier. Cilia can usually be noted
on the ventricular surface of ependyma. The distinction between choroid
plexus and ependymal cells can be seen at high magnification. E, In the#

spinal cord, a central collection of poorly organized ependymal cells forms
the vestigial central canal, which can sometimes be mistaken for a neoplasm
in small biopsy specimens. F, Extensions of the ependymal lining (arrow) can
sometimes be noted within the white matter at a distance from the
ventricular system, especially in the occipital lobe.
Choroid Plexus
The choroid plexus is a functionally di1erentiated region of ependyma that extends into the
ventricular space as frondlike tufts of epithelium that secrete the ultra ltrate of CSF (see Fig. 2-4).
Individual cells are found as a single layer on a brovascular core. Compared with ependyma,
they have larger, cobblestone-shaped cell bodies and contain small bland, basally located nuclei.
Microvilli extend from the apical surface. Tight junctions and desmosomes are present between
choroid plexus cells to ensure a viable blood–CSF barrier.
Microglia are small, elongated cells located throughout the CNS gray and white matter (Fig. 2-5).
In the resting state, microglia are easily overlooked because of their small size and bland
appearance, yet they account for nearly 20% of the cellular population. In standard H&E
sections, the nuclei of activated microglia are long, thin, and dark—leading to their designation as
“rod-cells”—but their cytoplasm is di cult to visualize. Special stains based on silver carbonate
or lectins provide contrast to small processes and delicate branches that extend from their tips.
Microglia are not neuroepithelial in origin, but rather are derived from a monocyte–macrophage
lineage that incorporates into the CNS early in development. Once established, they serve as
antigen-presenting cells for immune surveillance and participate in inEammatory responses,
particularly against viral pathogens.#
FIGURE 2-5 Microglia. A, Microglia have thin, elongated, and
hyperchromatic nuclei that stand out from the neuropil (arrow). Microglia are
most readily identified in their reactive state, when they are referred to as
“rod cells.” B, The rodlike quality of activated microglia is also appreciated on
cytologic preparations (arrows).
On activation, microglia proliferate and migrate to sites of damage, and in this state
(“microgliosis”), cells are more readily identi ed. Activation also causes increased expression of
proteins such as major histocompatibility complex (MHC) I and II, which can be detected
immunohistochemically. When microglia and astrocytes aggregate around a central focus of
injury, such as a virally infected neuron, they form a microglial nodule. Another population of
monocyte–macrophage-derived cells resides in the perivascular compartment, between the outer
basement membrane of the vessel and the glia limitans. As distinguished from parenchymal
microglia, these perivascular macrophages are in continuity with the circulating monocyte
population. Both perivascular and circulating populations of monocytes are recruited into the
CNS parenchyma in response to severe injury, where they di1erentiate into tissue macrophages,
often with foamy clear cytoplasm (a.k.a. gitter cells) in order to perform phagocytic and#
immunologic functions. They are sometimes referred to as the “garbage collectors” of the CNS,
since they clean up all necrotic debris, metabolic byproducts, and foreign material.
Blood Vessels
Similar to other organs, the brain has a population of vascular and perivascular cells essential for
its oxygen and nutrient supply. Compared with their extracranial counterparts, the large arteries
that run within the subarachnoid space have thinner muscular walls, less adventitia, and lack
external elastic lamina (Fig. 2-6). As they penetrate into the brain parenchyma, larger arteries
retain both a thin covering by the pia-arachnoid and a perivascular space, the Virchow-Robin
space, which represents a continuation of the subarachnoid space, although its function and
content remain controversial. No such space exists once the vessels become small capillaries and
the endothelium is intimately associated with neuropil. Capillaries are formed by individual
endothelial cells forming delicate tubular structures with widths suitable only for passage of
individual circulating blood cells. The physiologically critical blood–brain barrier is formed
predominantly by the specialized nature of CNS endothelial cell junctions and cannot be
identi ed histologically. In particular, these endothelial cells lack fenestrations between them
and are joined by specialized tight junctions that functionally preclude the free movement of
substances between vascular and CNS spaces. Astrocytic end-feet and basal lamina elements
contribute to the integrity of this blood–brain barrier.FIGURE 2-6 Blood vessels. A, Large arteries within the subarachnoid
space supply the brain by penetrating into the parenchyma, where initially
they maintain a perivascular space (Virchow-Robin space) that separates the
vessel from the neuropil (arrow). B, Smaller capillaries (arrows) within the
brain consist of a thin, delicate tube lined by a single layer of endothelial cells
that either directly abut the brain parenchyma or have a smaller perivascular
space. The blood–brain barrier is due in large part to the specialized tight
junctions between endothelial cells.
Meningothelial Cells
Meningothelial cells are scattered within the arachnoid membranes throughout the neuroaxis, but
they are most concentrated at the tips of arachnoid granulations and the outermost layers of the
arachnoid just under the adjacent dura, where they are called arachnoid cap cells (Fig. 2-7A and
B). Meningothelial cells are epithelioid to slightly spindled and are typically seen in small
clusters (10–20 cells), where they have a tendency to form whorls and psammoma bodies, similar
to their neoplastic counterparts in meningiomas. Cells have moderate amounts of eosinophilic
cytoplasm and oval nuclei with dispersed chromatin, often giving the appearance of centralclearing.
FIGURE 2-7 Meningothelial cells and melanocytes. A, Meningothelial cells
are scattered within the arachnoid membranes and are most frequent within
the outermost layers as arachnoid cap cells. They are typically spindled to
polygonal, have moderate amounts of eosinophilic cytoplasm and bland oval
nuclei, and usually occur in small clusters. B, Melanocytes (arrowheads) are
infrequent, flattened, highly pigmented cells of the pia and arachnoid
membranes that are generally dispersed individually and are in highest
density over the ventral brainstem. Meningothelial cells often form small
whorls at the outer surface of the arachnoid membranes (arrow). C, High
magnification of melanocytes.
Melanocytes are normal, neural crest-derived constituents of the human leptomeninges that are
intimately associated with pia and subarach- noid membranes (Fig. 2-7B and C). They are widely
scattered in most supratentorial regions and are noted histologically only following intense#
searching or fortuitous tissue sectioning. Their highest density is over the ventral surface of the
superior spinal cord, brainstem, and base of the brain. Almost always seen as individual
dendriteshaped cells rather than clusters, leptomeningeal melanocytes are thin, elongated, and show
slight branching and pigmentation in proportion to cutaneous pigmentation. As such, these cells
are often most conspicuous in African American patients. Melanin pigment is made within
cytoplasmic melanosomes and premelanosomes and is therefore similar to dermal melanocytes
rather than the neuromelanin of the substantia nigra.
Tissue Organization
Cerebral Cortex
The vast majority (>90%) of cerebral cortex in humans is neocortex, an evolutionarily late
form of cortical development that is distinguished from paleocortex (mostly limbic and olfactory
cortices) and archicortex (hippocampal structures), which are more primitive. Neocortex di1ers
from primitive cortex in its anatomic location and architecture. All neocortical areas—also called
isocortex—go through developmental periods in which their elements are laid down in six layers.
Many regions retain this layered appearance throughout life. Paleo- and archicortex do not share
this developmental pattern or six-layered structuring into adulthood.
Cerebral cortex contains two dominant neuronal types: the granular (stellate) cell and the
pyramidal cell (see section on Neurons). Pyramidal cells account for two thirds of cerebral cortical
neurons and are the primary output. They have prominent apical dendrites that extend toward
the cortical surface. Their axons extend long distances to terminate within the ipsilateral or
contralateral cortex or travel to subcortical regions. Granular cells are smaller and are considered
to be the primary interneurons of the neocortex. Other less common neurons are the horizontal
cells (of Cajal), common in the super cial cortex in development; fusiform cells, most frequent in
the deepest cortical layers; and cells of Martinotti, present in lesser numbers in all cortical layers.
The practice of neuropathology requires basic familiarity with neocortical structure (Fig. 2-8A),
since subtle abnormalities underlie diseases such as developmental migration disorders, cortical
dysplasia, epilepsy, neurodegenerative diseases, and hypoxic–ischemic injury (see Chapters 23
through 25). The six layers of the cortex, from the surface to the white matter, are (I) the
molecular layer, which has very few neurons in adulthood; (II) outer granular cell layer; (III)
outer pyramidal cell layer; (IV) inner granular cell layer; (V) inner pyramidal cell layer; and (VI)
multiforme layer, which is populated primarily by fusiform neurons. These layers are more
histologically apparent in some regions than others, often best appreciated in considerably
thicker sections than are normally cut for routine surgical neuropathology. Regions with primary
output function, such as primary motor cortex, have mostly pyramidal cells, whereas regions
with primarily integrating or sensory function contain mainly granular cells. In either instance,
dominance by a single cell type results in less apparent layering due to a loss of architectural
contrast. Regions with nearly equal compliments of granular and pyramidal cells demonstrate
the most apparent horizontal layering.
FIGURE 2-8 Cerebral cortex. A, Cerebral neocortex (isocortex) contains six
layers, numbered sequentially from superficial to deep: I, molecular layer; II,
external granular cell layer; III, external pyramidal cell layer; IV, internal
granular cell layer; V, internal pyramidal cell layer; VI, multiforme layer. WM,
white matter. B, The primary visual cortex of the occipital lobe has a
distinctive histologic arrangement. Cortical layer IV is greatly expanded due
to the high number of visual inputs and is divided into layers IVa, IVb, and
IVc. Prominent bands of Baillarger are present in layers IV and V in primary
visual cortex. The greatly expanded band of Baillarger in layer IV can be
seen grossly as the line of Gennari.
Myelin staining of the cortex reveals parallel, horizontal bands of myelinated bers that are
not as readily apparent on H&E-stained sections. The two most prominent bands are in layers IV
and V and are referred to as the external and internal bands of Baillarger, respectively. Primary
visual cortex (Brodmann’s area 17), located on either side of the calcarine ssure in the occipital
lobe, is characterized by a greatly widened band of Baillarger in layer IV due to the large input
of visual a1erent bers from the lateral geniculate nucleus (Fig. 2-8B). This enlarged zone
divides layer IV into three distinct layers and can be seen grossly as the “line of Gennari.”
White Matter
The white matter of the CNS is relatively uniform (Fig. 2-9A). It is generally more deeply
eosinophilic than the overlying cortex, and its matrix is coarser. Its architecture is dictated by the
arrays of axonal processes that extend to and from gray matter structures. Individual axons
themselves are di cult to appreciate on H&E sections of normal brain since they are thin and
blend with the background neuropil (though they can be noted in disease states in which neuropil
is disrupted). However, neuro lament immunohistochemistry or silver stains can highlight axons
(Fig. 2-9B). Oligodendrocytes, brillary astrocytes, and microglia are all oriented along the
length of axons with a fairly rigid periodicity. When viewed in the plane of white matter tracts,
units of approximately 5 to 10 oligodendrocytes are disposed in linear, parallel arrays along
axonal processes and interrupted by single interspersed brillary astrocytes. Microglia are also
located at regular intervals, albeit with much less frequency than oligodendrocytes, with cell#
bodies oriented parallel to axons.
FIGURE 2-9 White matter. A, Sweeping linear arrays of axons are the
backbone of the white matter but cannot be readily identified on hematoxylin
and eosin stains. Oligodendrocytes, astrocytes, and microglia are dispersed
linearly along the length of axons with a fairly rigid periodicity. B, Axons in the
white matter are highlighted in black by silver staining.
Basal Ganglia
The caudate, putamen, and the nucleus accumbens (a.k.a. the neostriatum) are developmentally
related and histologically similar (Fig. 2-10A). They contain a variety of small- and large-sized
neuronal populations that have relatively uniform density. About 95% are small- and
mediumsized (10–18 μm) γ-aminobutyric acid (GABA)-ergic spiny neurons that provide projections to the
globus pallidus (a.k.a. the paleostriatum). These have extensive dendritic trees packed with spines
for connection with the large array of input bers from the cerebral cortex, thalamus, and
brainstem. Other populations consist of large cholinergic neurons (approximately 2% of neurons)
and smaller cells containing neuropeptide Y, somatostatin, or nitric oxide synthetase.
Interspersed among the neurons and neuropil of the striatum are small white matter bundles of
the internal capsule that can only be seen microscopically. These “pencil bers of Wilson” are
specific for this region and serve as a guide to location when included in small biopsy specimens.#
FIGURE 2-10 Basal ganglia and thalamus. A, The caudate, putamen, and
globus pallidus contain a variety of small- and medium-sized neurons
interspersed in a rich neuropil. Pencil fibers of Wilson are small white matter
bundles embedded within the gray matter neuropil that are unique to these
deep nuclei of the cerebrum (arrow). B, The thalamus has large projection
neurons as well as a less frequent population of smaller, inhibitory
The thalamus is the main integrator and relay of sensory information to the cortex and has over
50 individual nuclei, each with its own speci c function. Classic divisions are the anterior,
medial, ventrolateral, and posterior groups of nuclei. Not among these larger categories are the
midline, intralaminar, and reticular nuclei. The histologic appearance of each of the lobes is
relatively similar, with variations depending on speci c functions (Fig. 2-10B). Thalamic neurons
consist of two main types: large projection neurons with axons that exit the thalamus (75% of
the neuronal population), and smaller, inhibitory (GABAergic) interneurons. Each large
projection neuron extends its process to the cerebral cortex through the internal capsule.
The hippocampal formation consists of the hippocampus proper, subiculum, and dentate gyrus
(a.k.a. dentate fascia) and is intimately associated with the entorhinal cortex (Fig. 2-11). The
entorhinal cortex occupies most of the parahippocampal gyrus, is the largest source of input into
the hippocampus, and contains a distinctive six-layered cortical architecture. Near its surface in
layer II are numerous large round neuronal clusters that can be seen as small protrusions on the
brain’s surface. Deeper are the remainder of its six layers that contain pyramidal cells and a
diverse array of smaller neurons. The subiculum sits at the base of the hippocampus and is a eld
populated largely by pyramidal neurons with an allocortical arrangement that transitions from
the three-layered cortex of the hippocampal cornu ammonis 1 (CA1) subdivision at one end to the
six-layered entorhinal cortex at the other. The hippocampus is divided into CA1, CA2, and CA3#
sub elds, each having distinct arrangements of pyramidal neurons and selective vulnerabilities
to disease. CA3 emerges from the hilum (a.k.a. CA4) of the dentate gyrus and contains the largest
pyramidal neurons. Pyramidal neurons of CA2 form a narrow band that runs between CA1 and
CA3. Transition to CA1 is characterized by a wider band of slightly smaller pyramidal neurons
that are more dispersed. CA1 (a.k.a. Sommer’s sector) is generally much more sensitive to
hypoxia, toxicants, seizures, and degenerative diseases than other sub elds. The molecular layer
of the hippocampal CA elds faces the dentate gyrus, and its white matter tracts form the alveus
that runs along the space between the CA neurons and the lateral ventricle. White matter tracts
of the alveus converge to form the mbria of the hippocampus, which continues as the fornix,
traveling around the peripheral portions of the septum pellucidum of the lateral ventricles to find
their way to the hypothalamus and mamillary bodies; this anatomic tract is also known as the
circuit of Papez and forms an important portion of the limbic system.
FIGURE 2-11 Hippocampal formation. The hippocampus proper consists of
CA1, CA2, and CA3 sectors of pyramidal neurons. CA1 continues as the
subiculum (SUB) at the base of the hippocampal formation. The dentate
fascia (DF) contains a narrow, densely populated band of granular cells
(stratum granulosum), which surrounds the hilum (H), or CA4. The major
white matter tract emerging from the hippocampus is the alveus (ALV),
located between hippocampal pyramidal fields and the lateral ventricle.
The densely packed smaller granular cells that form the C-shaped structure of the dentate gyrus
is the stratum granulosum. Hilar (or CA4) neurons that occupy the inner space within the
Cshaped structure formed by the dentate fascia are a heterogeneous population of neurons
including large pyramidal and smaller interneurons.
Pineal Gland#
The pineal gland has a unique morphology, unlike any other region in the CNS (Fig. 2-12). At
low magni cation, it has a lobulated arrangement with a prominent intralobular brovascular and
glial stroma. The cellularity of the normal pineal is greater than most regions, which together with
the unusual architecture, can lead to misinterpretation of this structure as a neoplasm. The
dominant cell type, the pineocyte is a medium-sized specialized neuronal cell with round, regular
“neuroendocrine” nuclei and delicate stippled chromatin. Pineocytes contain moderate amounts
of pale pink cytoplasm with short processes and form small clusters and linear arrays. They stain
avidly with synaptophysin and neuro lament protein antibodies, the latter of which often
demonstrates small club-shaped swellings. At the periphery of nests and surrounding blood
vessels is a higher density of brillarity. Interspersed among the nests and within the
perivascular region are the less common pineal astrocytes, which are highlighted with GFAP
FIGURE 2-12 Pineal gland. A, The pineal gland (arrow) is located in the
midline, posterior and superior to the midbrain tectum (asterisk). B, It
consists of loose lobules of pineocytes arranged in small clusters and linear
arrays and separated by glial and fibrovascular septae.
Pituitary Gland
The relationship between normal pituitary histology and disease is also covered in part in
Chapter 18. The pituitary gland is composed of anterior, intermediate, and posterior lobes (Fig.
2-13). The anterior and intermediate lobes (adenohypophysis) have di1ering embryology,
functions, and microscopic appearances from that of the posterior lobe (neurohypophysis). The
adenohypophysis is not of neuroectodermal origin, but rather is derived from oral ectoderm
which invaginates superiorly as Rathke pouch to eventually nd its place within the sellar
compartment. Notwithstanding their non-CNS origin, diseases of the sellar space often a1ect
neurologic function.FIGURE 2-13 Pituitary gland. A, B, The anterior pituitary gland consists of
tightly packed acini of acidophils (pink), basophils (blue), and chromophobes
(amphophilic) separated by a fine fibrovascular stroma. C, The posterior
pituitary (neurohypophysis) is formed by the axonal projections of neurons
from the hypothalamus together with primary glial cells and pituicytes, which
are most commonly located in a perivascular distribution. D, Eosinophilic
axonal dilations that store neurosecretory peptides (Herring bodies, arrow)
can be seen distributed throughout the posterior gland. E, The intermediate
lobe is small and often shows mild fibrosis, along with cysts (arrow) lined by
flattened, Rathke-type epithelium.
The pituitary gland is connected to the more superior hypothalamus by the pituitary stalk, which
is composed of the infundibulum, a superior extension of the neurohypophysis, and the pars
tuberalis, an extension of the anterior gland. The stalk also carries a functionally vital vascular
supply between hypophyseal and hypothalamic compartments. Arterial supplies to the pituitary
are the inferior and superior pituitary arteries, which branch from each internal carotid artery.
These give rise to a network of capillary loops within the gland (gomitoli), which in turn lead to
a substantial network of venous sinuses that drain back to the hypothalamus, carrying vital#
hormonal feedback. Thus, the vascular network of the pituitary is extensive and critical to
endocrine function.
The anterior pituitary accounts for over 75% of the sellar volume. It is composed of variably
sized nests, or acini, interrupted by stromal and vascular septa (Fig. 2-13A and B). Most are lled
with cellular elements and lack appreciable lumina. Only occasionally are glands with central
spaces noted, some containing mucinous or colloid content. Stroma surrounding individual acini
can be highlighted by reticulin stains, a helpful adjunctive test for establishing a normal glandular
arrangement and ruling out an adenoma. Individual cells of the anterior lobe are classi ed as
acidophils (40%), basophils (10%), and chromophobes (50%) based on their H&E staining. These
staining patterns are not absolutely speci c for endocrine function or hormone production (see
Chapter 18 for general patterns). Rather, glandular cells are more often classi ed based on their
immunohistochemical staining properties as lactotrophs (prolactin), thyrotrophs (thryrotrophic
hormone, TSH), somatotrophs (growth hormone, GH), corticotrophs (adrenocorticotrophic
hormone, ACTH), or gonadotrophs (follicle-stimulating hormone, FSH or leutinizing hormone,
LH). Whereas gonadotrophs are di1usely spread throughout the gland with even density, other
hormone-producing cells show regional variation. Corticotrophs and thyrotrophs are located in
highest density within the central portion of the gland, and lactotrophs and somatotrophs are in
highest density laterally.
The thin intermediate lobe of the pituitary is derived from the posterior Rathke cleft. In humans,
it is not well developed and contains only glandular and colloid- lled cystic remnants within a
slightly brous stroma. Individual cells are cuboidal or columnar, some with apical cilia, others
containing cytoplasmic mucin. When large or clinically symptomatic, these cystic spaces are
termed Rathke cleft cysts (Fig. 2-13E).
As distinguished from the glandular anterior lobe, the posterior pituitary, or neurohypophysis, is
an extension of the CNS and has a “neural” histology (Fig. 2-13C). It is composed of neuronal
processes that extend from their cell bodies in the hypothalamus down the pituitary stalk
(infundibulum) to occupy the posterior portion of the sella and terminate near blood vessels.
Scattered in the neuropil are Herring bodies—subtle esosinophilic axonal dilations that are lled
with lysosomes and neurosecretory granules containing vasopressin and oxytocin (Fig. 2-13D).
The most prominent nucleated cells of the neurohypophysis are pituicytes: GFAP-expressing
spindle or stellate glial cells that abut the basal lamina of blood vessels. Their cytoplasm engulfs
the nerve terminals and regulates the release of hormones into the bloodstream. The overall
histology of the neurohypophysis is complex, with a seemingly disorganized cell arrangement
that includes sweeping axonal processes punctuated by more cellular perivascular regions,
causing occasional confusion with neoplastic disease.
Although the circuitry of the cerebellar cortex is exceedingly intricate, its histologic appearance is
homogeneous and relatively simple throughout (Fig. 2-14). Outermost is the molecular layer, a
rich neuropil network containing abundant axonal and dendritic processes, but only a few small
neuronal cell bodies. The Purkinje cell layer is at the junction of the molecular layer and the
deeper granular cell layer (see Figs. 2-1E and 2-3G arrows). Purkinje cells are large neurons that
have widely arborizing dendritic trees that extend into the molecular layer, serving as synaptic
input for the parallel bers of the granular cells. Purkinje cell axons are the main output of the
cerebellar cortex, and a majority terminate on the neurons of the dentate nucleus. Granular cells
of the cerebellum are the most common neuronal cell in the CNS and are present in a high-#
density region central to Purkinje cells. Each granular cell sends an axon to the molecular layer,
which then bifurcates to form the parallel bers that synapse with numerous Purkinje cell
dendritic trees.
FIGURE 2-14 Cerebellum. The cerebellar cortex contains a sparsely
cellular molecular layer (ML), a Purkinje cell layer (PCL), a granular cell layer
(GCL), and white matter (WM).
The deep cerebellar nuclei are set on either side of the midline cerebellum in the midst of the
white matter tracts of the medullary center that are entering and leaving cerebellar cortex. These
are seen as thin, undulating ribbons of gray matter containing large and small neurons. Within
the gray matter ribbon is a central zone of white matter tracts that projects out of the
cerebellum. The largest and most lateral nucleus is the dentate nucleus, which has both
developmental ties and morphologic similarity to the inferior olive of the medulla. It is the source
of most e1erent signals traveling out of the cerebellum via the superior peduncle. The other deep
cerebellar nuclei, from lateral to medial, are the emboliform, globose, and fastigial nuclei.
Throughout the brainstem, anatomic regions are broadly subdivided, from ventral to dorsal, as
base, tegmentum, and tectum. The base is located ventrally and consists mostly of long white
matter tracts (cerebral peduncles, basis pontis, and medullary pyramids). The tegmentum lies
dorsal to the base and ventral to the cerebral aqueduct or fourth ventricle. Among other
structures, it contains the reticular formation, an area of centrally located, relatively uniform
gray matter that lacks strict organization and boundaries but is critical to the control of basal
bodily activities, including cardiovascular tone, respiration, and consciousness. The tectum is the
area located dorsal to the brainstem ventricular compartments, serving as their roof. Together,
the tectum and tegmentum house most of the integrative and cranial nerve nuclei components of
the brainstem.
The locations of cranial nerve nuclei display the same general pattern throughout the
brainstem. Nuclei are located in the dorsal tegmentum in the vicinity of the fourth ventricle.#
Motor nuclei are located medially, sensory nuclei are located laterally, and the autonomic nuclei
are found between them.
At the most ventral aspect of the midbrain are the large cerebral peduncles. These dense white
matter bundles occur on both sides of the midbrain and are composed predominantly of
inferiorly projecting corticospinal and corticopontine bers. Immediately dorsal is the substantia
nigra (SN), a thin strip that extends laterally and dorsally from the midline and contains large,
heavily pigmented dopaminergic neurons (Fig. 2-1G, 2-15A). In the midline between the right
and left SN is the ventral tegmental area, where there is a functionally discreet population of
pigmented dopaminergic neurons. The red nuclei are paired, round gray matter structures dorsal
to the SN in the rostral midbrain. Around the ependymal-lined cerebral aqueduct is the
periaqueductal gray matter, a collection of neurons involved in pain modulation. The midbrain
tectum is almost entirely composed of inferior and superior colliculi, and the tegmentum contains
predominantly white matter structures.#
FIGURE 2-15 Brainstem. A, In the midbrain, the substantia nigra is
composed of the reticulata (SNr), which resembles basal ganglia
histologically, and the compacta (SNc), which contains a high density of large
pigmented dopaminergic neurons. Ventral to the SNr is the cerebral
peduncle (CP), and dorsal to the SNc in the superior midbrain is the red
nucleus (RN). B, The base of the pons contains numerous, prominent
pontine crossing fibers (arrow) that intertwine with pontine nuclei (asterisk)
and descending fibers (arrowhead), including corticospinal tracts (Luxol fast
blue stain). C, The medulla contains the inferior olivary nucleus (arrow),
which like the related dentate nucleus in the cerebellum, is made of a thin
ribbon of undulating gray matter surrounding a white matter hilum (Luxol fast
blue/PAS stain).
The pons is dominated by its large base (basal pons or basis pontis) and by its large white matter
connections to the cerebellum: the superior, middle, and inferior cerebellar peduncles. The basal
pons consists of both transversely and longitudinally oriented white matter tracts (Fig. 2-15B).
Longitudinal bers include corticospinal tracts that continue as the medullary pyramids and#
corticopontine tracts that terminate on the interspersed pontine nuclei. The eye-catching
transverse bers represent white matter bundles arising from pontine nuclei, crossing the
midline, and entering the cerebellum via the middle cerebellar peduncle. Near the fourth ventricle
on each side of the pons is the locus ceruleus (“blue spot”), a small nucleus containing a high
density of pigmented, noradrenergic neurons that project di1usely throughout the CNS. Near the
midline throughout the brainstem, but concentrated mostly in the dorsal pons, are the midline
raphe nuclei (midline “seam”). These nuclei contain large serotonergic neurons that project
extensively throughout the brain.
Anterior in the medulla are the paired medullary pyramids, which carry corticospinal tracts to
their decussation at the medullary-spinal junction, then continue as the lateral corticospinal tracts
in the spinal cord. Posterior to the pyramids in the midline is the medial lemniscus, a white matter
tract projecting from the contralateral cuneate and gracile nuclei. More lateral in the rostral
medulla are the dominant olivary nuclei, seen as bulges (olives) on the anterolateral medullary
surface (Fig. 2-15C). This ovoid structure consists of a ribbon of convoluted gray matter with
large pyramidal-type neurons surrounding a hilus of outwardly projecting white matter tracts
that extend to the contralateral cerebellar peduncle. The olivary nucleus is developmentally and
functionally related to the cerebellar dentate nucleus and resembles it histologically. Posteriorly,
the fasciculus gracilis and cuneatus are continuations of the posterior columns and terminate in
the nucleus gracilis and nucleus cuneatus, respectively. The medial longitudinal fasciculus is a white
matter tract that rides the midline dorsally, while the spinothalamic tract maintains its
anterolateral position in the brainstem, immediately dorsal to the olive in the medulla.
Spinal Cord
The spinal cord has the same basic histologic organization throughout its length, with unique
features superimposed at speci c spinal levels (Fig. 2-16). On cross section the cord contains
central gray matter in the shape of an H and surrounding white matter tracts. The white matter
tracts are functionally diverse and precisely organized in terms of sensory and motor function.
Nonetheless, they are fairly uniform in histologic cross sections, showing mostly bundles of
myelinated and unmyelinated bers traveling in the superior–inferior direction with scattered
oligodendrocytes and brillary astrocytes. Anterior horns are the ventral extensions of the
Hshaped gray matter and contain the large anterior horn cells (lower motor neurons) and smaller
gamma motor neurons, which innervate muscle spindles. Anterior horns are the largest and
contain the greatest number of lower motor neurons at the cervical and lumbar enlargements
due to their output to the arms and legs. The posterior horn contains large projection neurons and
smaller interneurons. The substantia gelatinosa is a posteriorly located portion of the posterior
horn that is distinguished by its lack of myelinated bers, giving rise to its pale appearance. It
continues dorsally into Lissauer’s tract, another poorly myelinated region of white matter.#
FIGURE 2-16 Spinal cord. Cross section of the thoracic spinal cord shows
anterior horns (AH), posterior horns (PH), intermediolateral cell columns
(IML), white matter (WM), the ependymal-lined central canal (CC),
substantia gelatinosa (SG), Lissauer’s tract (LT), the fasciculus gracilis (FG)
of the dorsal columns, anterior spinal artery (ASA), ventral roots (VR) and
dorsal roots (DR).
The gray matter region between anterior and posterior horns contains cells of the autonomic
nervous system. Between levels T1 and L3 is located the intermediolateral cell column, which
extends o1 the central gray matter as a lateral horn. It contains the cell bodies of preganglionic
sympathetic neurons, which project out through the ventral roots. The intermediate zone from S2
to S4 contains mostly a parasympathetic neuronal population. Lastly, Clarke’s nucleus is a medial
extension of the intermediate gray matter found from spinal levels T1 to L2. It contains large
neurons important to sensory processing with the cerebellum.
The dura mater has a histologic appearance unlike any other region of the nervous system (Fig.
217). It consists of a thick, monotonous layer of dense brous connective tissue composed mostly
of layered collagen with only scattered interspersed Eattened broblasts. Because its appearance
is so consistent, its identi cation within a histologic section ensures the pathologist that the
location of the surgically sampled lesion was super cial (i.e., near or involving the dural
covering); nonetheless, some caution is warranted since markedly brotic leptomeninges may
occasionally approach the thickness of dura. Normally, however, the arachnoid membranes that
traverse the space between dura and underlying brain contains the arachnoid trabeculae, which
are a delicate meshwork of thin connective tissue containing Eattened broblast-like cells,
scattered meningothelial cells, and rare melanocytes (see Figs. 2-7, 2-17B). The most super cial
layer of cells (arachnoid cap cells) forms a continuous lining that is tethered to the overlying
dura and forms a restrictive barrier to the Eow of Euids between the subarachnoid space and the
dura. Normally, there is in fact no subdural space per se, but these relatively weak attachments
between arachnoid and dura are easily disrupted or pealed back by hemorrhage (e.g., subdural
hematoma) or “unnatural” forces, such as the prying hands of a surgeon or pathologist. The pial#
layer is found on the surface of the brain as a delicate brous coating that is slightly eosinophilic
compared with the underlying cortex and contains only rare small Eattened cells (Fig. 2-17C). It
extends peripherally to fuse with the overlying arachnoid trabeculae to form a continuous pia–
arachnoid network.FIGURE 2-17 Meninges. A, The dura mater is a thick, dense, fibrous
connective tissue covering for the brain with low cellularity. B, The arachnoid
membranes are delicate fibrous bands (arrow) that traverse the
subarachnoid space (asterisk), embed subarachnoid vessels, and have
attachments to both underlying pia and overlying dura. C, The pia mater
(arrow) is a thin, fine coating on the surface of the brain that is brightly
eosinophilic and merges with the arachnoid.#
Peripheral Nerve, Schwann Cells, and Dorsal Root Ganglia
Within millimeters of their exit from the CNS, both cranial nerves and spinal nerve roots
transition from a central to a peripheral nerve morphology and myelinating pattern (with the
exception of cranial nerve VIII, which transitions at the internal auditory meatus) (see also
Chapter 22). Schwann cells are the glial cell equivalents of the peripheral nervous system that
provide an insulating coat of myelin around axons to improve conduction speeds (Fig. 2-18A).
Larger nerves (e.g., sural nerve) typically have multiple subunits known as fascicles, which
appear rounded on cross section and consist of ensheathed bundles of myelinated and
unmyelinated axons, along with Schwann cells, small blood vessels, and stromal support.
Together with peripheral nerve broblasts and the collagen-rich network of endoneurium (within
the fascicle), perineurium (surrounding individual fascicles), and epineurium (surrounding the
entire nerve), Schwann cells provide a structural support to their underlying axonal processes. In
contrast to oligodendrocytes, the myelin-rich cytoplasm of a single Schwann cell is Eattened and
concentrically laminated around a segment of a large axon at speci c intervals between nodes of
Ranvier. In standard H&E-stained tissue sections Schwann cells are the most numerous cell bodies
within peripheral nerves and are seen in longitudinal sections as elongated, spindled cells
containing cigar-shaped hyperchromatic nuclei. On cross section of nerve, their myelin-rich
coating is seen as a clear, donut-shaped ring around a central, tiny, eosinophilic axon (Fig.
218B). Stains for myelin (Luxol fast blue) dramatically improve the visibility of the myelin sheath.
FIGURE 2-18 Dorsal root ganglia and peripheral nerve. A, Peripheral nerve
in longitudinal plane showing bundles of axons (arrow), which are only barely
visible within their thicker, clear myelin sheath. Schwann cells have elongate
nuclei with slightly bulbous ends and are oriented along the length of the
axon to provide its myelination. B, On transverse section of a peripheral
nerve, the clear ring of bubbly myelin is seen surrounding a central zone
occupied by the axon (arrow). C, Each large neuronal cell body (ganglion
cell) of the dorsal root ganglion is surrounded by satellite cells—a specialized
Schwann cell population.
Dorsal root ganglia are located near the spinal exit foramina, invested within a dural sheath,
and are the home of cell bodies for spinal a1erent sensory neurons. Individual cell bodies of
ganglion cells are large, with abundant cytoplasm, Nissl substance, prominent vesicular nuclei,
large nucleoli, and variable quantities of cytoplasmic lipofuscin pigment (Fig. 2-18C). Peripheral
extensions terminate in transducing sensory receptors that give rise to incoming signals. Large,
long processes extend centrally via the dorsal roots into the spinal cord, with the largest#
myelinated tracts becoming the ascending posterior columns. Around the perimeter of each
ganglion cell body are slender satellite cells (specialized Schwann cells), which most likely serve a
support role and provide a committed stem cell source for repopulation of their more peripheral
Features of Infancy and Childhood
The germinal matrix is a neural stem cell population that is adjacent to the lateral ventricles as a
subependymal layer and gives rise to sequentially di1erentiated neuronal and glial precursors
that migrate to their homes in the cerebrum (Fig. 2-19A). The germinal matrix is prominent in
early brain development and does not begin to thin out until the 26th week of gestation. The
matrix persists as scattered cell islands and perivascular nests until term. After birth, most of the
germinal matrix disappears except for a portion called the ganglionic eminence, which is located
between the thalamus and caudate. It fragments and diminishes in size throughout the rst year
of life.
FIGURE 2-19 Features of development and infancy. A, The germinal matrix
(GM) is a periventricular precursor cell population located directly adjacent to
the ependyma (E) of the lateral ventricles (LV). Although heavily populated
by neural precursors during fetal development, it diminishes and eventually
disappears in the first year of postnatal life (germinal matrix of
20-weekgestation fetus). Neural precursors migrate away from the germinal matrix to
eventually populate the cerebral hemispheres with mature neuronal and glial
populations (arrow). B, The cerebral cortex undergoes gradual lamination
during fetal development, with individual layers emerging in the fifth month of
gestation. The cortex of a 30-week-gestation fetus shows a clearly formed
molecular layer (ML), initial separation of cerebrocortical layers (CC), and
demarcation of the cortex from white matter (WM). C, The fetal and infant
cerebellum contains an external granular cell layer (EGCL, arrow), which is a
precursor cell population that migrates inward through the molecular layer
(ML) to form the internal granular cell layer (IGCL) (cerebellum of 6-week-old
infant). WM, white matter.
The cerebral cortex derives from neuroblasts that migrate outwardly along radial glia from the
germinal matrix. The inner-most neurons of the cortex are the first to arrive and are subsequently
joined by neuroblasts migrating to progressively more super cial regions. By the fth month of
fetal development, the cortex shows a super cial molecular layer and a deeper, densely cellular
band (Fig. 2-19B). From the latter, a six-layered cortex gradually emerges starting in the sixth
month. Cortical layering results from the maturation of cortical laminar neurons, the selective#
cell death of neuronal populations, and expansion of the neuropil due to the growth of dendritic
Cerebellar cortical development occurs along two major pathways. The Purkinje cells form early
in embryonic life after migrating to their nal location from the alar plate. Granular cells
develop from the rhombic lip. They rst form a precursor population as the external granular cell
layer, which is located at the surface of the cerebellar folia, super cial to the molecular cell layer.
External granular cells are actively dividing and give rise to inwardly migrating cells that form
the internal granular cell layer—the granular cell population that persists in adulthood (Fig.
219C). Although the external granular cell layer begins to diminish at 2 to 3 months after birth, it
does not totally disappear until 12 months.
Features of the Aging Nervous System
A wide range of histologic features may be encountered in the aging nervous system, often
becoming most prominent in elderly patients; they are summarized in Box 2-1 and illustrated in
Figures 2-20 and 2-21. Recognition of these structures is critical in order to avoid misinterpreting
them as pathologic. In the case of neuro brillary tangles (Fig. 2-21A) and neuritic plaques
(221B), the distinction between normal aging and disease becomes a matter of quantity and
location. Small numbers of tangles in the mesial temporal lobe are considered part of normal
aging, but widespread neocortical involvement is a sign of Alzheimer’s disease (AD), and
extensive subcortical deposits are characteristic of other neurodegenerative disorders, such as
progressive supranuclear palsy (see Chapter 25). In fact, the precise number and type of neuritic
plaques (and tangles) needed for a de nitive diagnosis of AD has been a topic of great debate
over the years, although fortunately most cases of advanced disease contain numerous
widespread plaques and tangles, making the diagnosis relatively straight-forward. Similarly,
while corpora amylacea (Fig. 2-20A) are extremely common and are considered totally
innocuous, similar structures may be seen within neuronal cells or their processes in rare
disorders such as Lafora’s disease and adult polyglucosan body disease.FIGURE 2-20 Findings of normal aging. A, Corpora amylacea (arrow) are
spherical basophilic polyglucosan bodies that accumulate as astrocytic
inclusions during the aging process. Their highest density is around blood
vessels, under the pial surface, and adjacent to the ventricles—locations
where astrocytic foot processes are most common. These eye-catching
laminated bodies are not always recognized as being intracellular, and they
can accumulate to striking densities. B, Perivascular mineralization of the
large vessels of the globus pallidus (arrow) is a common aging process and
can begin as early as childhood. C, Microvascular mineralization also occurs
with increasing age and is seen most frequently in the hippocampus and the
basal ganglia (arrow). D, The arachnoid membranes become thicker and
more fibrous with age. Fibrous plaques are thick, densely hyalinized forms of
fibrosis that occur in the most superficial layer of the arachnoid membranes.
These are noted most often over the median aspects of the superior frontal
and parietal lobes and the covering of the spinal cord.FIGURE 2-21 Findings that may occur in limited fashion in normal aging. A,
Neurofibrillary tangles are slightly basophilic, crystalline inclusions that fill the
neuronal cytoplasm, generally taking the shape of a flame (arrows). B,
Amyloid plaques represent the extracellular accumulation of β-amyloid that
deposits as part of aging or Alzheimer disease (arrow). C, Granulovacuolar
degeneration consists of small cytoplasmic vacuoles and basophilic granules
and is noted most often in the hippocampal pyramidal cells of elderly
individuals (arrows).
21 Fea tures of Ag ing
Neurofibrillary tangles
Granulovacuolar degeneration
Hirano bodies
Neuritic plaques
Marinesco bodies
Lipofuscin accumulation
Pigment incontinence of substantia nigra
Corpora amylacea adjacent to ependyma, subpial regions, and vasculature
Fibrous thickening
Hyaline plaques
Arachnoid granulation collagenization (Pacchionian bodies)
Meningothelial hyperplasia (reactive proliferation)
Psammoma body formation
Pituitary Gland
Squamous cell metaplasia of pars tuberalis
Adenohypophyseal fibrosis
Perivascular mineralization, globus pallidusMicronodular mineralization, globus pallidus and hippocampal molecular layer
Choroid plexus mineralization and cystic change
Pineal mineralization and cystic change
Suggested Readings
Nolte, J. The Human Brain: An Introduction to Its Functional Anatomy, 5th ed. St. Louis: Mosby,
Fuller, G. N., Burger, P. C. Central nervous system. In Mills S.E., ed.: Histology for Pathologists, 3rd
ed, Philadelphia: Lippincott Williams & Wilkins, 2007.
Ortiz-Hildago, C., Weller, R. O. Peripheral nervous system. In Mills S.E., ed.: Histology for
Pathologists, 3rd ed, Philadelphia: Lippincott Williams & Wilkins, 2007.
Lopes, M. B.S., Pernicone, P. J., Scheithauer, B. W., . Pituitary and sellar region. In Mills S.E.,
ed.: Histology for Pathologists, 3rd ed, Philadelphia: Lippincott Williams & Wilkins, 2007.
Kandel, E.R., Schwartz, J.H., Jessell, T.M. Principles of Neural Science, 4th ed. New York:
McGraw-Hill, 2000.
Friede, R.L. Developmental Neuropathology, 2nd ed. Berlin: Springer-Verlag, 1989.
Nelson, J.S., Mena, H., Parisi, J.E., Schochet, S.S. Principles and Practice of Neuropathology, 2nd
ed. New York: Oxford University Press, 2003.
Intraoperative Consultation and
Optimal Processing
Gregory N. Fuller
Types of Neurosurgical Specimens  35
Intraoperative Cytologic Preparations as a Complement to Frozen Tissue
Sections  36
Fixation and Staining Options for Intraoperative Cytologic Preparations  36
Frozen Sectioning of Central Nervous System Tissue  36
Artifacts  37
Iatrogenically Introduced Hemostatic and Embolic Agents  42
The Bottom Line: What Does the Surgeon Need to Know?  42
Intraoperative consultation is unquestionably one of the most important and often most
challenging tasks for the surgical pathologist. Of all the organ systems, neurosurgical specimens
1appear to be particularly problematic. Each surgical specimen and clinical setting o ers its own
unique challenge. Nevertheless, some time-tested principles can be applied in virtually all
situations to provide the most reliable diagnostic interpretation. In this chapter the various
aspects of intraoperative surgical neuropathology will be explored, with an emphasis on
practical techniques and approaches.
Types of Neurosurgical Specimens
The physical size of tissue specimens submitted for frozen section evaluation varies greatly (Box
3-1). Specimen size is directly related to the goal of the surgical procedure. Endoscopic and
stereotactic biopsies are typically performed for diagnostic purposes only, whereas at the other
end of the spectrum, hemispherectomies and lobectomies are often performed for surgical cure
under the best of circumstances. Between these two extremes lies a large range of specimen sizes
encompassed by open biopsies, partial resections, and gross total resections. Despite this variation in
specimen size, some general principles are more or less universally applicable (Box 3-2). The two
most helpful rules are (1) perform a cytologic preparation as a complement to the frozen tissue
section, and (2) never freeze all of the lesional tissue; that is, always save some tissue for
formalin- xed para. n-embedded (FFPE) permanent sections. A rare exception to the latter rule occurs
when the surgeon had intended to obtain additional tissue for optimal preservation, but was
unable due to intraoperative complications that arose.
31 Surg ica l Specimen Size, Genera lly Arra ng ed from Sma llest toLa rg est
Endoscopic biopsy
Stereotactic biopsy
Open biopsy
Partial resection
Gross total resection
32 Genera l Principles for Ha ndling Intra opera tive Consulta tion
Tissue Specimens
Perform a cytologic preparation as a complement to the frozen tissue section.
Don’t freeze all of the tissue.
Don’t submit the entire specimen for para. n embedding (save some in glutaraldehyde or
For minute biopsy specimens, cut unstained slides from the frozen section block and order
unstained sections from the para. n blocks up front in order to avoid loss of diagnostic tissue
when refacing the block.
Sometimes, de- nitive tumor is identi- ed on the frozen section but unusual or unexpected
morphologic features are apparent. In such cases it is prudent, if su. cient tissue is available, to
place a small representative fragment in glutaraldehyde for ultrastructural examination, if
needed. If glutaraldehyde is not available, retaining a small amount of tissue in formalin is the
next best option. Retrieving tissue from para. n blocks followed by post- xation and processing
for electron microscopy is possible, but often yields suboptimal ultrastructural detail.
The pathologist is sometimes faced with a situation in which a minute stereotactic biopsy tissue
fragment has been entirely frozen and reveals the presence of neoplasm or other lesional tissue,
but immunostaining will likely be required for further classi- cation or grading. If the surgeon is
reluctant to take additional tissue cores due to the risk of intracranial hemorrhage (a rare
scenario when good preoperative planning has happened and open communication exists with
the pathologist), it is advisable to have unstained tissue sections cut from the frozen section block
before removing it from the cryostat, since there is no guarantee that lesional tissue will still be
present in the para. n block after processing and refacing. Similarly, if small biopsy cores are
provided by the surgeon for permanent sections, it is prudent to request unstained sections
initially (i.e., cut at the same time as the section for hematoxylin and eosin (H&E) staining) in
order to avoid loss of lesional tissue secondary to block refacing.
An additional safeguard in the setting of scant lesional tissue is the preparation of several
unstained cytologic touch preparations from the fresh tissue before submitting for processing.
Intraoperative Cytologic Preparations as a Complement to Frozen
Tissue Sections
At some institutions, historical practices have dictated that only frozen sections are performed for
intraoperative consultation; at others, intraoperative diagnoses are made primarily by cytologic
preparation, with frozen sections being only rarely employed. However, a large number of

surgical neuropathologists worldwide routinely use a combination of cytologic preparations and
frozen sections to render intraoperative diagnoses, and these two procedures are viewed as
complementary, with the cytologic preparation providing exquisite nuclear and cytoplasmic
detail free of freeze artifact and distortion, and the frozen section providing architectural details,
including the relationship between the disease process and the host tissue (e.g., solid versus
2–7infiltrative tumor).
Several types of technical procedures are available for generating the cytologic preparation
and the choice depends on a number of factors, including the disease type and the consistency of
the tissue submitted for intraoperative evaluation (Box 3-3). For example, touch (imprint)
preparations are generally optimal for pituitary adenoma. The concept is to take advantage of an
integral aspect of adenoma pathobiology—the clonal expansion of loosely cohesive adenoma
cells together with the attendant e acement and loss of the - brovascular septa that
compartmentalize normal adenohypophyseal tissue into acini. Adenoma cells tend to shed
profusely on touch preparations compared with normal adenohypophysis. Touch preparations
also work well on other hypercellular, loosely cohesive or dishesive tumors, such as lymphoma
and melanoma. However, for more cohesive neoplasms and disease processes, the touch
preparation is frequently hypocellular and often consists primarily of uninformative red blood
cells. For this reason, many pathologists prefer the smear (squash, crush) preparation for soft tissue
specimens, including most primary and metastatic central nervous system (CNS) tumors.
33 Types of Intra opera tive Cytolog ic Prepa ra tions
Touch (imprint)
Smear (squash, crush)
Cytologic preparations are of particular value for speci- c problematic tissue specimens (Table
3-1). The pathologist sometimes receives a minute biopsy specimen that is too small to divide into
separate portions for cytologic smear and frozen tissue section. In such cases, the tissue fragment
can be - rst dragged across a slide to yield a cytologic preparation (cytologic drag preparation)
before freezing. Another problematic specimen is the extensively cauterized tissue fragment.
Although some of these may be beyond salvage, an attempt at diagnosis can be made by
bisecting the tissue and performing a cytologic drag preparation before freezing the tissue.
Fibrous or desmoplastic tissue samples often do not smear well. In such situations, a scrape
preparation may be optimal. With this procedure, the tissue is grasped with forceps and a scalpel
blade repeatedly drawn across the surface. The collected debris is then spread across a glass slide.
Another challenging situation is presented by a Petri dish full of grossly necrotic tissue fragments.
Arbitrarily choosing one or two fragments for frozen section often yields only nonspeci- c
necrosis. In this situation, it is advantageous to sample as much tissue as possible for any viable
tumor cells or cell clusters, yet preparing 10 or 20 frozen sections is impractical. One solution is
to perform a cytologic drag preparation on multiple tissue fragments. With this procedure, one
fragment after another is quickly dragged across the same, single slide; 5, 10, 15 or more
fragments can be sampled in a matter of only seconds. If any viable tumor cells are present, this
procedure is an e. cient and cost-e ective way to maximize the chances of their detection.
Occasionally the pathologist is confronted with a request for “frozen section” on a specimen

consisting of bony fragments, without an identi- able soft tissue component. An attempt to obtain
a diagnosis can be made by performing a cytologic drag preparation of the bony fragments; this
may yield a diagnostic preparation for some pathologic processes, such as metastatic carcinoma.
Table 3-1
Problematic Frozen Section Specimens
Tissue Recommended Handling
Minute sample Perform a cytologic touch or drag preparation before freezing the
(endoscopic or tissue fragment.
stereotactic biopsy)
Cauterized tissue Bisect with scalpel and perform a cytologic drag preparation of the
fragment freshly cut surface before freezing the tissue.
Fibrous or desmoplastic Perform a cytologic scrape preparation before freezing the tissue.
Petri dish full of necrotic Perform a cytologic drag preparation using multiple (10-15) tissue
tissue fragments fragments on the same slide to maximize sampling for viable
tumor cells.
Bony tissue fragments Perform a cytologic drag preparation.
submitted for “frozen
Fixation and Staining Options for Intraoperative Cytologic
Depending on the background, experience, and personal preference of the pathologist, cytologic
preparations may either be air-dried or immersed immediately in 95% ethanol to avoid drying
artifact. For gliomas in particular, the latter method provides superior preservation since nuclear
cytology is particularly critical and air drying often produces marked artifacts of size, shape, and
chromatin density. Similarly, stain preference varies among pathologists, although many prefer
routine H&E. At some institutions, the preference is to perform an initial rapid one-step Di -
Quick stain on the first cytology slide, followed by routine H&E staining of a second preparation.
Frozen Sectioning of Central Nervous System Tissue
Many pathologic processes that involve the CNS, including di use gliomas and metastatic
tumors, elicit marked vasogenic edema of brain parenchyma that is most pronounced in the
white matter. This increase in water content of an already very soft and lipid-rich tissue can lead
to pronounced freeze artifact, often severe enough to signi- cantly impede or even prevent
diagnosis. In general, the optimal conditions for cryostat sectioning of brain tissue may not be
the same as those used for other tissue types. Experimentation with block temperature and
section thickness may reduce artifact. In addition, cutting two or three serial sections onto the
slide can be helpful. An additional strategy to reduce the formation of large ice crystals is to
make sure the specimen freezes rapidly. Snap freezing is the most common means for achieving
such rapid freezing and is performed by - rst immersing the specimen (surrounded by a smallamount of optimal cutting temperature [OCT] compound on a metal chuck) into an isopentane
cryobath. Once the chuck is transferred to the cryostat, additional OCT is added and a metal heat
extractor is quickly placed on top, simultaneously creating a more rapid freeze and a Gat cutting
surface. Frozen tissue sections of CNS tissue can be obtained in a quality that approaches FFPE
tissue sections in quality, but optimizing the procedure may require practice, experimentation,
and close collaboration between pathologist and histotechnician.
A number of artifacts can interfere with frozen section diagnosis (Box 3-4). Some artifacts can
impede or even prevent interpretation, whereas others can mislead the pathologist into
rendering an inaccurate diagnosis. Chief among the artifacts that can make reliable diagnosis
impossible are freeze and cautery artifacts. The former can be minimized as described in the
prior section. Cautery artifact, on the other hand, is out of the pathologist’s control. Some
specimens, usually minute tissue fragments, are completely uninterpretable (Fig. 3-1A); others
may be salvaged by judicious selection of the least cauterized areas for freezing. Even in areas
where the tissue is less severely cauterized, however, artifacts may lead to misinterpretation. For
instance, nuclei appear thinner and more elongate, often polarizing in the same direction (Fig.
31B). This can give a false sense of astrocytic, - brous, or schwannian cytology with associated
palisading or pseudopalisading. As a general rule, whenever cauterized vessels are identi- ed by
their characteristic smudgy purple walls and dark pyknotic nuclei, the surrounding brain
parenchyma must be interpreted with extreme caution because minor, misleading distortions of
nuclear and cellular morphology may not appear to be artifact (Fig. 3-1C).FIGURE 3-1 Cautery artifact. Cautery artifact ranges from severe and
uninterpretable (A) to mild and misleading (B, C). A, Severe cautery artifact
in which the distortion has rendered the tissue uninterpretable. B, Moderate
cautery artifact in which the nuclei are artifactually elongated and tend to
polarize in the same direction. A cauterized vessel is seen at the bottom of
the field. C, Mild cautery artifact with artifactually elongated nuclei. The
obviously cauterized vessels serve as a warning to the pathologist to
interpret the surrounding tissue with caution. Compare with an uncauterized
area of the same surgical specimen shown in D, which reveals the nuclei to
be rounded, without the artifactual elongation seen in cauterized areas of the
34 Artifa cts
Pseudocalcification (“bone dust”)
Pseudonecrosis (see Box 3-5)
“Blue sponge”
Formalin precipitate
Formic acid treatment
Dark cell change
Freeze artifact is also high on the list of misleading artifacts. Similar to cautery artifact, a
spectrum of tissue distortion from freezing can be seen, and may be virtually uninterpretable in
its most severe form (Fig. 3-2). Nuclear distortion and irregularity that result from freezing in
oligodendroglioma is a very common situation. The morphologic hallmark of this distinctive

di use glioma, as instantly recognized on FFPE sections, is a monotonous population of cells
with uniformly regular round nuclei surrounded by perinuclear halos. On frozen sections,
however, the perinuclear halos, which are themselves an artifact, albeit a useful one, resulting
from FFPE processing, are not present, and freezing also induces a varying degree of nuclear
irregularity and pleomorphism that is not seen in FFPE sections. The end result is that frozen
sections of oligodendroglioma tend to look like astrocytoma (Fig. 3-3A and B). Misinterpretation
of this artifact is a common cause of diagnostic discrepancy between frozen section
interpretation and - nal diagnosis. What can be done to avoid this pitfall? The cytologic
preparation may be helpful because it preserves oligodendroglioma features, with regular round
nuclei and delicate chromatin pattern beautifully displayed without the distortion induced by
freezing. But does the surgeon really need to know whether a di use glioma displays astrocytic,
oligodendroglial, or mixed oligoastrocytic di erentiation at the time of intraoperative
consultation? Will the answer change what the surgeon does? The answer in most instances is
“no.” It should be su. cient to convey that the disease process is a di use glioma, and if
highgrade features are present, that information can be conveyed as well; otherwise, the precise
classi- cation and grading of a di use glioma should await the superior morphology of FFPE
tissue sections and the results of adjunctive special studies. One exception to this rule arises when
the preoperative imaging studies and clinical information strongly suggest glioblastoma (e.g.,
magnetic resonance imaging [MRI] shows a ring-enhancing mass lesion crossing the corpus
callosum). Although a number of entities can manifest with these imaging features (glioblastoma,
lymphoma, abscess, demyelinating pseudotumor, etc.), once the pathologist has identi- ed the
presence of di use glioma on the frozen section, the likelihood that the surgical specimen is
representative should be assessed; speci- cally, can the histologic features seen account for the
contrast enhancement (i.e., microvascular proliferation) and central hypodensity (i.e., necrosis)
on the imaging studies? If not, additional tissue should be requested.
FIGURE 3-2 Freeze artifact. Similar to severe cautery artifact, severe
freeze artifact can also render brain tissue so distorted as to be virtually
uninterpretable.FIGURE 3-3 Freeze artifact. Freeze artifact distorts nuclear morphology
such that oligodendroglioma looks more like astrocytoma. A, B, In this frozen
section (A) of an oligodendroglioma, the artifactual nuclear distortion
produces irregular contours reminiscent of fibrillary astrocytoma. However,
the formalin-fixed paraffin-embedded permanent section (B) shows round
uniform nuclei.
The neurosurgeon may occasionally introduce an artifact of particles of “bone dust” into the
specimen. These microscopic fragments of cranial bone are generated during the drilling of burr
holes and the turning of craniotomy Gaps and - nd their way into the surgically resected tissue.
When arti- cially trapped between tissue fragments that have been pushed up against each other,
bone dust fragments mimic dystrophic calci- cation and can be mistaken as part of the disease
process, perhaps leading to an inaccurate conclusion that the disease is more chronic in nature
(Fig. 3-4A). Simple awareness of bone dust as a common contaminant in neurosurgical
specimens can signi- cantly mitigate the chance of misinterpretation. Surgical re-excision
specimens may contain bone dust from the prior operation that has become embedded in reactive
scar tissue, often with an associated foreign body-type giant cell reaction (Fig. 3-4B).FIGURE 3-4 Bone dust. A, Microscopic fragments of cranial bone are seen
artifactually surrounded by resected tissue, which can convey the mistaken
impression of dystrophic calcification and lesion chronicity. B, At subsequent
repeat surgery, bone dust fragments can be seen incarcerated in reactive
fibrous tissue, often accompanied by a foreign body-type giant cell reaction.
Also seen in this field of resected dura are suture fibers from a previous
Necrosis is a key diagnostic - nding in many disease processes. The misidenti- cation of
necrosis in a specimen can lead to serious inaccuracies in diagnosis. A number of artifacts can
lead to “pseudonecrosis” (Box 3-5). Among the most common is a simple technical staining error
yielding focal absence of hematoxylin staining, often seen at the end of the slide in smear
preparations or frozen tissue sections. The resultant bright eosin staining of tissue protein
without hematoxylin staining of nuclear nucleic acid mimics the dissolution of nucleic acid seen
in necrotic tissue (Fig. 3-5).
FIGURE 3-5 Pseudonecrosis. A common cause of pseudonecrosis is
absence of hematoxylin staining (usually near the end of the slide) due to
technical error. In this smear preparation, the right side of the smear
preparation is brightly eosinophilic, mimicking necrosis. At high power, no
necrosis was seen, only lack of hematoxylin staining.
35 Pseudonecrosis Artifa cts
No hematoxylin
Cerebellar molecular layer
Degenerating hemostatic agent (especially microfibrillar collagen)
Cavitational ultrasonic surgical aspirator (CUSA, Cavitron) artifact
Severe freeze artifact
Formic acid overdigestion
Focal hemorrhage or fibrin deposition within CNS tissue can sometimes be misinterpreted as
necrotic foci and result in, for example, overgrading of a di use astrocytoma as glioblastoma
(Fig. 3-6). The absence of karyorrhectic nuclei is one clue favoring a conclusion of
pseudonecrosis.FIGURE 3-6 Red blood cell pooling and fibrin deposition mimicking
necrosis. Hemorrhage with red blood cell pooling and fibrin deposition within
a diffuse glioma can mimic necrosis to the unwary, potentially leading to
overgrading. The obvious intact red blood cells seen at the far edge of this
photomicrograph will not always be present to alert the pathologist to the
One normal CNS region that often mimics necrosis on smear preparations and frozen sections
is the cerebellar cortex. The brightly eosinophilic, hypocellular molecular layer stands out in sharp
chiaroscuro when juxtaposed against the densely hypercellular, hematoxylinophilic granular cell
layer. This appearance has fooled more than one pathologist into an impression of necrosis,
sometimes with attendant misinterpretation of the small granular cell layer neurons as
metastatic small cell carcinoma or lymphoma. This mimicry is further heightened by freeze
artifact (Fig. 3-7).FIGURE 3-7 Cerebellar cortex molecular layer mimicking necrosis. The
cerebellar cortex is striking in its juxtaposition of the hypocellular outer
molecular layer and hypercellular granular cell layer, as exemplified in this
frozen section. The sharp contrast in cellularity and staining characteristics
can lead to the mistaken interpretation of the molecular layer as necrosis on
smear preparations and frozen sections, with the “small cell” features of the
granular cell layer potentially being mistaken for metastatic small cell
carcinoma, lymphoma, or medulloblastoma.
One iatrogenically introduced form of pseudonecrosis artifact is caused by degenerating
hemostatic agent. Foreign material introduced by the surgeon or interventional radiologist as a
source of tissue artifact is discussed in more detail in the following section.
Another source of pseudonecrosis is the artifact produced in tissue fragments that are obtained
through ultrasound-induced tissue cavitation followed by suction removal (cavitational ultrasonic
surgical aspiration, or CUSA). The resulting specimen, usually received in a saline-- lled suction
collection bag, is a mixture of intact and mechanically disrupted or partially autolytic tissue
fragments, bone dust, blood, and hemostatic material. The distorted tissue fragments, altered by
both the suction process and saline immersion, can simulate necrosis (“CUSA artifacts”) (Fig.
38). The pathologist must be careful not to overinterpret such specimens, but rather carefully
search for relatively intact fragments that can be reliably interpreted.FIGURE 3-8 Pseudonecrosis. Pseudonecrosis is a common artifact seen in
tissue specimens obtained by cavitational ultrasonic surgical aspiration
(CUSA). This field from a CUSA specimen nicely illustrates the distorted
nuclei of pseudonecrosis in comparison with an adjacent fragment of
relatively preserved brain parenchyma.
Because of its soft consistency, brain specimens are much more susceptible to mechanical
distortions during surgery (e.g., crush artifacts from forceful use of surgical instruments), during
handling by the pathologist (e.g., crush artifacts from forceps), or even during tissue processing.
In terms of the last circumstance, a common artifact results from tissue placed into cassettes
between blue sponges in order to prevent loss of small fragments of tissue (“blue sponge artifact”)
(Fig. 3-9A). Given the - nger-like projections of these sponges, the permanent sections often
reveal triangular “clear holes” in the tissue, with signi- cant crush artifact at the edges of these
holes. Similarly, biopsy embedding bags can parcellate small brain biopsy specimens into a
checkerboard of small tissue squares (Fig. 3-9B). Particularly with small specimens, such as those
retrieved in stereotactic needle biopsies, these processing techniques may leave little
wellpreserved tissue to examine. Therefore, careful wrapping of small brain specimens in wax paper
or the use of cassettes with very small windows are preferable methods for minimizing tissue loss
during routine processing.